SUBSTITUTED ISINDOLIN-1-ONES AND 2,3-DIHYDRO-1H-PYRROLO[3,3-c]PYRIDIN-1-ONES AS HPK1 ANTAGONISTS

ABSTRACT

The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of HPK1, and the treatment of HPK1-mediated disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application No. 62/900,152, filed Sep. 13, 2019 and U.S.Provisional Application No. 63/032,070, filed May 29, 2020, the contentsof each of which is incorporated herein in its entirety by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful forantagonizing hematopoietic progenitor kinase 1 (HPK1). The inventionalso provides pharmaceutically acceptable compositions comprisingcompounds of the present invention and methods of using saidcompositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

The hematopoietic progenitor kinase 1 (HPK1), otherwise known as mitogenactivated protein kinase kinase kinase kinase 1 (MAP4K1), is ahematopoietic cell-restricted member of the Ste20 serine/threoninekinase super family. The MAP4Ks family includes MAP4K1/HPK1, MAP4K2/GCK,MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS, and MAP4K6/MINK. HPK1 is atissue-specific upstream activator of the MEKK/JNK/SAPK signalingpathway.

HPK1 is of particular interest because it is predominantly expressed inhematopoietic cells such as T cells, B cells, macrophages, dendriticcells, neutrophils, and mast cells (Hu, M. C., et al., Genes Dev, 1996.10(18): p. 2251-64; Kiefer, F., et al., EMBO J, 1996. 15(24): p.7013-25). HPK1 kinase activity has been shown to be induced uponactivation of T cell receptors (TCR) (Liou, J., et al., Immunity, 2000.12(4): p. 399-408), B cell receptors (BCR) (Liou, J., et al., Immunity,2000. 12(4): p. 399-408), transforming growth factor receptor (TGF-PR)(Wang, W., et al., J Biol Chem, 1997. 272(36): p. 22771-5; Zhou, G., etal., J Biol Chem, 1999. 27-((19): p. 13133-8), or Gs-coupled PGE2receptors (EP2 and EP4) (Ikegami, R., et al., J Immunol, 2001. 166(7):p. 4689-96). As such, HPK1 regulates diverse functions of various immunecells. HPK1 is also an example of a negative regulator of dendritic cellactivation, and T and B cell responses that can be targeted to enhanceanti-tumor immunity. HPK1 is expressed predominantly by hematopoieticcells, including early progenitors. In T cells, it is believed that HPK1negatively regulates T cell activation by reducing the persistence ofsignaling microclusters by phosphorylating SLP76 at Ser376 (Di Bartoloet al. (2007) JEM 204:681-691) and Gads at Thr254, which leads to therecruitment of 14-3-3 proteins that bind to the phosphorylated SLP76 andGads, releasing the SLP76-Gads-14-3-3 complex from LAT-containingmicroclusters (Lasserre et al. (2011) J Cell Biol 195(5):839-853). HPK1can also become activated in response to prostaglandin E2, which isoften secreted by tumors, contributing to the escape of tumor cells fromthe immune system.

HPK1 is important in regulating the functions of various immune cellsand it has been implicated in autoimmune diseases and anti-tumorimmunity (Shui, J. W., et al., Nat Immunol, 2007. 8(1): p. 84-91; Wang,X., et al., J Biol Chem, 2012. 287(14): p. 11037-48).

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asantagonists of HPK1. In certain embodiments, the invention provides forcompounds of the formulae presented herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with regulation of signalingpathways implicating HPK1 kinases. Such diseases, disorders, orconditions include those described herein.

Compounds provided by this invention are also useful for the study ofHPK1 enzymes in biological and pathological phenomena; the study ofintracellular signal transduction pathways occurring in bodily tissues;and the comparative evaluation of new HPK1 inhibitors or otherregulators of kinases, signaling pathways, and cytokine levels in vitroor in vivo.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCertain Embodiments of the Invention

In certain aspects, the present invention provides a compound of formulaI

or a pharmaceutically acceptable salt thereof, wherein each of X, Z, R¹,R², R³, and m, is as defined below and described in embodiments herein,both singly and in combination.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a compound of formula I and a pharmaceuticallyacceptable carrier, adjuvant, or diluent.

In some embodiments, the present invention provides a method of treatinga HPK1-mediated disease, disorder, or condition comprising administeringto a patient in need thereof, a compound of formula I, or apharmaceutically acceptable salt thereof 2. Compounds and Definitions:

Compounds of the present invention include those described generallyherein, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. For purposes of this invention,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,75^(th) Ed. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th)Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,the entire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

As used herein, the term “bridged bicyclic” refers to any bicyclic ringsystem, i.e. carbocyclic or heterocyclic, saturated or partiallyunsaturated, having at least one bridge. As defined by IUPAC, a “bridge”is an unbranched chain of atoms or an atom or a valence bond connectingtwo bridgeheads, where a “bridgehead” is any skeletal atom of the ringsystem which is bonded to three or more skeletal atoms (excludinghydrogen). In some embodiments, a bridged bicyclic group has 7-12 ringmembers and 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Such bridged bicyclic groups are well known in theart and include those groups set forth below where each group isattached to the rest of the molecule at any substitutable carbon ornitrogen atom. Unless otherwise specified, a bridged bicyclic group isoptionally substituted with one or more substituents as set forth foraliphatic groups. Additionally or alternatively, any substitutablenitrogen of a bridged bicyclic group is optionally substituted.Exemplary bridged bicyclics include:

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where unless otherwise specified, the radical orpoint of attachment is on the heteroaromatic ring or on one of the ringsto which the heteroaromatic ring is fused. Nonlimiting examples includeindolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl,indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl groupmay be mono- or bicyclic. The term “heteroaryl” may be usedinterchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or“heteroaromatic,” any of which terms include rings that are optionallysubstituted. The term “heteroaralkyl” refers to an alkyl groupsubstituted by a heteroaryl, wherein the alkyl and heteroaryl portionsindependently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or ^(+NR (as in N-substituted pyrrolidinyl).)

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl,2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms“heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—N(R^(∘))C(NR^(∘))N(R^(∘))₂, —(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘);—(CH₂)₀₋₄C(O)OR^(∘); (CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃;—(CH₂)₀₋₄OC(O)R^(∘); —OC(O)(CH₂)₀₋₄ SR^(∘); —SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘))₂; —C(S)SR^(∘);—SC(S)SR^(∘), —(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘);—C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘); C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘);—(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘);—S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘)S(O)₂NR^(∘))₂;—N(R^(∘)S(O)₂R^(∘); —N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; P(O)₂R^(∘);—P(O)R^(∘))₂; —OP(O)R^(∘))₂; —OP(O)(OR^(∘))₂; —SiR^(∘) ₃; —(C₁₋₄straight or branched alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight orbranched)alkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substitutedas defined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(•), (haloR^(•)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•), —(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂ SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂ NHR^(•), —(CH₂)₀₋₂ NR^(•)₂, —NO₂, —SiR^(•) ₃, —OSiR^(•) ₃, —C(O)SR^(•), —(C₁₋₄ straight orbranched alkylene)C(O)OR^(•), or —SSR^(•) wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR^(*)₂, ═NNHC(O)R^(*), ═NNHC(O)OR^(*), ═NNHS(O)₂R^(*), ═NR^(*), ═NOR^(*),—O(C(R^(*) ₂))₂₋₃O—, or —S(C(R^(*) ₂))₂₋₃S—, wherein each independentoccurrence of R^(*) is selected from hydrogen, C₁₋₆ aliphatic which maybe substituted as defined below, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. Suitabledivalent substituents that are bound to vicinal substitutable carbons ofan “optionally substituted” group include: —O(CR^(*) ₂)₂₋₃O—, whereineach independent occurrence of R^(*) is selected from hydrogen, C₁₋₆aliphatic which may be substituted as defined below, or an unsubstituted5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(*) include halogen,R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ salts. Representative alkalior alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention. In certainembodiments, a warhead moiety, R¹, of a provided compound comprises oneor more deuterium atoms. In certain embodiments, Ring B of a providedcompound may be substituted with one or more deuterium atoms.

The structures as drawn represent relative configurations, unlesslabeled as absolute configurations. The invention contemplatesindividual enantiomers and racemic mixtures.

As used herein, a “HPK1 antagonist” or a “HPK1 inhibitor” is a moleculethat reduces, inhibits, or otherwise diminishes one or more of thebiological activities of HPK1 (e.g., serine/threonine kinase activity,recruitment to the TCR complex upon TCR activation, interaction with aprotein binding partner, such as SLP76). Antagonism using the HPK1antagonist does not necessarily indicate a total elimination of the HPK1activity. Instead, the activity could decrease by a statisticallysignificant amount including, for example, a decrease of at least about5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,75%, 80%, 85%, 95% or 100% of the activity of HPK1 compared to anappropriate control. In some embodiments, the HPK1 antagonist reduces,inhibits, or otherwise diminishes the serine/threonine kinase activityof HPK1. In some of these embodiments, the HPK1 antagonist reduces,inhibits, or otherwise diminishes the HPK1-mediated phosphorylation ofSLP76 and/or Gads. The presently disclosed compounds bind directly toHPK1 and inhibit its kinase activity.

By “specific antagonist” is intended an agent that reduces, inhibits, orotherwise diminishes the activity of a defined target greater than thatof an unrelated target. For example, a HPK1 specific antagonist reducesat least one biological activity of HPK1 by an amount that isstatistically greater than the inhibitory effect of the antagonist onany other protein (e.g., other serine/threonine kinases). In someembodiments, the IC₅₀ of the antagonist for the target is about 90%,80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1%, 0.1%, 0.01%, 0.001% orless of the IC₅₀ of the antagonist for a non-target. The presentlydisclosed compounds may or may not be a specific HPK1 antagonist. Aspecific HPK1 antagonist reduces the biological activity of HPK1 by anamount that is statistically greater than the inhibitory effect of theantagonist on any other protein (e.g., other serine/threonine kinases).In certain embodiments, the HPK1 antagonist specifically inhibits theserine/threonine kinase activity of HPK1. In some of these embodiments,the IC₅₀ of the HPK1 antagonist for HPK1 is about 90%, 80%, 70%, 60%,50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001%, or less of the IC₅₀ of theHPK1 antagonist for another serine/threonine kinase or other type ofkinase (e.g., tyrosine kinase).

A compound of the present invention may be tethered to a detectablemoiety. It will be appreciated that such compounds are useful as imagingagents. One of ordinary skill in the art will recognize that adetectable moiety may be attached to a provided compound via a suitablesubstituent. As used herein, the term “suitable substituent” refers to amoiety that is capable of covalent attachment to a detectable moiety.Such moieties are well known to one of ordinary skill in the art andinclude groups containing, e.g., a carboxylate moiety, an amino moiety,a thiol moiety, or a hydroxyl moiety, to name but a few. It will beappreciated that such moieties may be directly attached to a providedcompound or via a tethering group, such as a bivalent saturated orunsaturated hydrocarbon chain. In some embodiments, such moieties may beattached via click chemistry. In some embodiments, such moieties may beattached via a 1,3-cycloaddition of an azide with an alkyne, optionallyin the presence of a copper catalyst. Methods of using click chemistryare known in the art and include those described by Rostovtsev et al.,Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., BioconjugateChem., 2006, 17, 52-57.

As used herein, the term “detectable moiety” is used interchangeablywith the term “label” and relates to any moiety capable of beingdetected, e.g., primary labels and secondary labels. Primary labels,such as radioisotopes (e.g., tritium, ³²P, ³³P, ³⁵S, or ¹⁴C), mass-tags,and fluorescent labels are signal generating reporter groups which canbe detected without further modifications. Detectable moieties alsoinclude luminescent and phosphorescent groups.

The term “secondary label” as used herein refers to moieties such asbiotin and various protein antigens that require the presence of asecond intermediate for production of a detectable signal. For biotin,the secondary intermediate may include streptavidin-enzyme conjugates.For antigen labels, secondary intermediates may include antibody-enzymeconjugates. Some fluorescent groups act as secondary labels because theytransfer energy to another group in the process of nonradiativefluorescent resonance energy transfer (FRET), and the second groupproduces the detected signal.

The terms “fluorescent label”, “fluorescent dye”, and “fluorophore” asused herein refer to moieties that absorb light energy at a definedexcitation wavelength and emit light energy at a different wavelength.Examples of fluorescent labels include, but are not limited to: AlexaFluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, AlexaFluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, AlexaFluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL,BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568,BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY650/665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue,Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5),Dansyl, Dapoxyl, Dialkylaminocoumarin,4′,5′-Dichloro-2′,7′-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin,Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800),JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin,Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, RhodamineGreen, Rhodamine Red, Rhodol Green,2′,4′,5′,7′-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine (TMR),Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

The term “mass-tag” as used herein refers to any moiety that is capableof being uniquely detected by virtue of its mass using mass spectrometry(MS) detection techniques. Examples of mass-tags include electrophorerelease tags such asN-[3-[4′-[(p-Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecoticAcid, 4′-[2,3,5,6-Tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone, and their derivatives. The synthesis and utility of thesemass-tags is described in U.S. Pat. Nos. 4,650,750, 4,709,016,5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270.Other examples of mass-tags include, but are not limited to,nucleotides, dideoxynucleotides, oligonucleotides of varying length andbase composition, oligopeptides, oligosaccharides, and other syntheticpolymers of varying length and monomer composition. A large variety oforganic molecules, both neutral and charged (biomolecules or syntheticcompounds) of an appropriate mass range (100-2000 Daltons) may also beused as mass-tags.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in a HPK1 protein kinase activitybetween a sample comprising a compound of the present invention, orcomposition thereof, and a HPK1 protein kinase, and an equivalent samplecomprising an HPK1 protein kinase, in the absence of said compound, orcomposition thereof.

3. Description of Exemplary Embodiments

As described above, in certain embodiments, the present inventionprovides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   Z is CR or N;-   X is a covalent bond, —O—, —S—, —NR—, —S(O)₂—, —S(O)₂NR—, —S(O)—,    —S(O)NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(O)N(R)O—, —OC(O)—,    —OC(O)NR—, —N(R)C(O)O—, —N(R)C(O)—, —N(R)S(O)₂—; or X is a C₁₋₄    bivalent saturated or unsaturated, straight or branched hydrocarbon    chain wherein one or two methylene units of the chain are optionally    and independently replaced by —C(R)₂—, —N(R)—, —N(R)C(O)—,    —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—,    —S—, —S(O)— or —S(O)₂—;-   R¹ is selected from C₁₋₆ aliphatic; phenyl; a 3-7 membered saturated    or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered    monocyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated    or partially unsaturated monocyclic heterocyclic ring having 1-2    heteroatoms independently selected from nitrogen, oxygen, and    sulfur; and an 8-10 membered saturated or partially unsaturated    bicyclic heterocyclic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur; each of which is    substituted with q instances of R^(C);-   R² is a 6-11 membered saturated, partially unsaturated, or    unsaturated fused, bridged, or spiro bicyclic ring having 0-3    heteroatoms independently selected from nitrogen, oxygen, and    sulfur; each of which is substituted with q instances of R^(C);-   each instance of R³ is independently hydrogen or an optionally    substituted C₁₋₆ aliphatic group;-   each instance of R^(C) is independently oxo, halogen, —CN, —NO₂,    —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R,    —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,    —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)NR₂, —N(R)S(O)₂NR₂,    —N(R)S(O)₂R, —N═S(O)R₂, —S(NR)(O)R, —N(R)S(O)R, —N(R)CN,    —P(O)(R)NR₂, —P(O)(R)OR or —P(O)R₂; or each instance of R^(C) is    independently an optionally substituted group selected from C₁₋₆    aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or    partially unsaturated monocyclic carbocyclic ring; a 3-7 membered    saturated or partially unsaturated monocyclic heterocyclic ring    having 1-2 heteroatoms independently selected from nitrogen, oxygen,    phosphorous, silicon and sulfur; or a 5-6 membered monocyclic    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl    ring having 1-5 heteroatoms independently selected from nitrogen,    oxygen, and sulfur; a 5-8 membered saturated or partially    unsaturated bridged bicyclic ring having 0-3 heteroatoms    independently selected from nitrogen, oxygen, and sulfur; a 6-11    membered saturated or partially unsaturated spirocyclic ring having    0-3 heteroatoms independently selected from nitrogen, oxygen, and    sulfur; or a 6-11 membered saturated or partially unsaturated    bicyclic heterocyclic ring having 1-3 heteroatoms independently    selected from nitrogen, oxygen, and sulfur; each of which is    substituted with r instances of R and s instances of R^(D);-   each instance of R^(D) is independently oxo, halogen, —CN, —NO₂,    —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R,    —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,    —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)NR₂, —N(R)S(O)₂NR₂,    —N(R)S(O)₂R, —N═S(O)R₂, —S(NR)(O)R, —N(R)S(O)R, —N(R)CN,    —P(O)(R)NR₂, —P(O)(R)OR or —P(O)R₂;-   each R is independently hydrogen, —CN, halogen, or an optionally    substituted group selected from C₁₋₆ aliphatic; phenyl;    naphthalenyl; a 3-7 membered saturated or partially unsaturated    monocyclic carbocyclic ring; a 3-7 membered saturated or partially    unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur; a 5-6    membered monocyclic heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur; an 8-10    membered bicyclic heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur; a 7-12    membered saturated or partially unsaturated bicyclic heterocyclic    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, and sulfur; a 5-8 membered saturated or partially    unsaturated bridged bicyclic ring having 0-3 heteroatoms    independently selected from nitrogen, oxygen, and sulfur; a 6-10    membered saturated or partially unsaturated spirocyclic ring having    0-3 heteroatoms independently selected from nitrogen, oxygen, and    sulfur; a 6-11 membered saturated or partially unsaturated bicyclic    carbocyclic ring having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur; or:-   two R groups on the same nitrogen are taken together with the    nitrogen to form an optionally substituted 4-7 membered monocyclic    saturated, partially unsaturated, or heteroaryl ring having, in    addition to the nitrogen, 0-3 heteroatoms independently selected    from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially    unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur;-   m is 0, 1, or 2;-   each q is independently 0, 1, 2, 3, or 4;-   each r is independently 0, 1, 2, 3, or 4; and-   each s is independently 0, 1, 2, 3, or 4.

As defined generally above, Z is CR or N.

In some embodiments. Z is CR. In some embodiments, Z is N.

In some embodiments, Z is CH. In some embodiments, Z is CCl. In someembodiments, Z is CF. In some embodiments, Z is CCH₃.

In some embodiments, Z is selected from those depicted in Table 1,below.

As defined generally above, X is a covalent bond, —O—, —S—, —NR—,—S(O)₂—, —S(O)₂NR—, —S(O)—, —S(O)NR—, —C(O)—, —C(O)O—, —C(O)NR—,—C(O)N(R)O—, —OC(O)—, —OC(O)NR—, —N(R)C(O)O—, —N(R)C(O)—, —N(R)S(O)₂—;or X is a C₁₋₄ bivalent saturated or unsaturated, straight or branchedhydrocarbon chain wherein one or two methylene units of the chain areoptionally and independently replaced by —C(R)₂—, —N(R)—, —N(R)C(O)—,—C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—,—S—, —S(O)— or —S(O)₂—.

In certain embodiments, X is —O—, —S—, —NR—, —S(O)₂—, —S(O)₂NR—, —S(O)—,—S(O)NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(O)N(R)O—, —OC(O)—, —OC(O)NR—,—N(R)C(O)O—, —N(R)C(O)—, —N(R)C(O)NR—, —N(R)C(NR)NR—, —N(R)NR—,—N(R)S(O)₂NR—, or —N(R)S(O)₂—.

In some embodiments, X is a C₁₋₄ bivalent saturated or unsaturated,straight or branched hydrocarbon chain wherein one or two methyleneunits of the chain are optionally and independently replaced by —C(R)₂—,—N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—,—OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)₂—.

In certain embodiments, X is —NR—, —C(O)—, —C(O)O—, —C(O)NR—,—C(O)N(R)O—, —OC(O)—, —OC(O)NR—, —N(R)C(O)O—, —N(R)C(O)—, —N(R)C(O)NR—,—N(R)C(NR)NR—, or —N(R)NR—.

In certain embodiments, X is —NR—. In certain embodiments, X is —NH—.

In some embodiments, X is selected from those depicted in Table 1,below.

As defined generally above, R¹ is selected from C₁₋₆ aliphatic; phenyl;a 3-7 membered saturated or partially unsaturated monocyclic carbocyclicring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; a 3-7 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur; and an 8-10 membered saturated or partially unsaturated bicyclicheterocyclic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; each of which is substituted with qinstances of R^(C).

In some embodiments, R¹ is C₁₋₆ aliphatic which is substituted with qinstances of R^(C); phenyl which is substituted with q instances ofR^(C); a 3-7 membered saturated or partially unsaturated monocycliccarbocyclic ring, which is substituted with q instances of R^(C); a 5-6membered monocyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, which is substituted with qinstances of R^(C); a 3-7 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, which is substituted with qinstances of R^(C); or an 8-10 membered saturated or partiallyunsaturated bicyclic heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; which issubstituted with q instances of R^(C).

In some embodiments, R¹ is phenyl or a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, each of which is substituted with qinstances of R^(C).

In certain embodiments, R¹ is phenyl, indanyl, tetrahydronaphthyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; -1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, oxetanyl, pyrimidinyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl,thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl;each of which is substituted by q instances of R^(C).

In certain embodiments, R¹ is phenyl, furanyl, furazanyl,imidazolidinyl, imidazolinyl, imidazolyl, isothiazolyl, isoxazolyl,morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; —1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl,oxetanyl, pyrimidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl,pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, thienyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,oxetanyl, azetidinyl, or xanthenyl; each of which is substituted by qinstances of R^(C).

In certain embodiments, R¹ is furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; —1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxetanyl,pyrimidinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2H-pyrrolyl, pyrrolyl, thiazolyl, thienyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, or 1,2,5-triazolyl, 1,3,4-triazolyl; each of which issubstituted by q instances of R^(C).

In certain embodiments, R¹ is phenyl, pyrazolyl, pyridinyl, pyrazinyl,or pyrimidinyl; each of which is substituted by q instances of R^(C).

In certain embodiments, R¹ is pyrazolyl or pyridinyl; each of which issubstituted by q instances of R^(C).

In certain embodiments, R¹ is pyrazolyl or pyridinyl; each of which issubstituted by q instances of R^(C); wherein each R^(C) is independentlyhalogen, —CN, —OR, —S(O)₂R, —C(O)NR₂, or each instance of R^(C) isindependently an optionally substituted group selected from C₁₋₆aliphatic; a 5-10 membered saturated or partially unsaturated bridgedbicyclic ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; a 6-12 membered saturated or partiallyunsaturated spirocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated orpartially unsaturated monocyclic carbocyclic ring; a 3-7 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen,phosphorous, silicon and sulfur; or two R^(C) groups together with theatoms to which each is attached, forms a bridged, fused, or spiro 5-6membered aryl ring, a 3-7 membered saturated or partially unsaturatedmonocyclic carbocyclic ring, a 3-7 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, phosphorous, silicon andsulfur; wherein each instance of R^(C) is independently optionallysubstituted by R and R^(D).

In certain embodiments, R¹ is

In certain embodiments, R¹ is

In certain embodiments, R¹ is

-   -   wherein each instance of R^(C) is independently a 3-7 membered        saturated or partially unsaturated monocyclic heterocyclic ring        having 1-2 heteroatoms independently selected from nitrogen,        oxygen, phosphorous, silicon and sulfur; or a 5-8 membered        saturated or partially unsaturated bridged bicyclic ring having        0-3 heteroatoms independently selected from nitrogen, oxygen,        and sulfur; each of which is substituted with r instances of R        and s instances of R^(D).

In certain embodiments, R¹ is

-   -   wherein each instance of R^(C) is independently -Me, -Et, —CN,        —F, —OMe, —S(O)₂Me,

In certain embodiments, R¹ together with its R^(C) substituents is

In certain embodiments, R¹ together with its R^(C) substituents is

In certain embodiments, R¹ together with its R^(C) substituents is

In some embodiments, R¹ is selected from those depicted in Table 1,below.

As defined generally above, R² is a 6-11 membered saturated, partiallyunsaturated, or unsaturated fused, bridged, or spiro bicyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur; each of which is substituted with q instances of R^(C).

In some embodiments, R² is a 6-11 membered saturated, partiallyunsaturated, or unsaturated fused, bridged, or spiro bicyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur; substituted with q instances of R^(C).

In certain embodiments, R² is a 7-10-membered fused bicyclic ring having1-3 nitrogen atoms; each of which is substituted by each of which issubstituted by q instances of R^(C).

In certain embodiments, R² is a 9-membered fused bicyclic ring having1-3 nitrogen atoms; each of which is substituted by each of which issubstituted by q instances of R^(C); wherein each R^(C) is independentlyhalogen, —CN, —OR, —C(O)NR₂, —NR₂; or each instance of R^(C) isindependently an optionally substituted group selected from C₁₋₆aliphatic; phenyl; a 3-7 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, phosphorous, silicon and sulfur; and a6-11 membered saturated or partially unsaturated fused, bridged, orspiro bicyclic heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; wherein each instance ofR^(C) is independently optionally substituted by r instances of R and sinstances of R^(D).

In certain embodiments, R² is

In certain embodiments, R² is

In certain embodiments, R² is

In certain embodiments, R² together with its R^(C) substituents is

In certain embodiments, R² together with its R^(C) substituents is

In some embodiments, R² is selected from those depicted in Table 1,below.

As defined generally above, each instance of R³ is independentlyhydrogen or an optionally substituted C₁₋₆ aliphatic group.

In some embodiments, R³ is hydrogen. In some embodiments, R³ is anoptionally substituted C₁₋₆ aliphatic group.

In some embodiments, R³ is methyl. In some embodiments, R³ is

In some embodiments, R³ is

In some embodiments, R³ is selected from those depicted in Table 1,below.

As defined generally above, each instance of R^(C) is independently oxo,halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,—S(O)NR₂, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,—N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)NR₂,—N(R)S(O)₂NR₂, —N(R)S(O)₂R, —N═S(O)R₂, —S(NR)(O)R, —N(R)S(O)R, —N(R)CN,—P(O)(R)NR₂, —P(O)(R)OR or —P(O)R₂; or each instance of R^(C) isindependently an optionally substituted group selected from C₁₋₆aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partiallyunsaturated monocyclic carbocyclic ring; a 3-7 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, phosphorous,silicon and sulfur; or a 5-6 membered monocyclic heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; a 5-8 memberedsaturated or partially unsaturated bridged bicyclic ring having 0-3heteroatoms independently selected from nitrogen, oxygen, and sulfur; a6-10 membered saturated or partially unsaturated spirocyclic ring having0-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur; or a 6-11 membered saturated or partially unsaturated bicyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; each of which is substituted with rinstances of R and s instances of R^(D).

In some embodiments, each instance of R^(C) is independently oxo,halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,—S(O)NR₂, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,—N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)NR₂,—N(R)S(O)₂NR₂, —N(R)S(O)₂R, —N═S(O)R₂, —S(NR)(O)R, —N(R)S(O)R, —N(R)CN,—P(O)(R)NR₂, —P(O)(R)OR or —P(O)R₂; or each instance of R^(C) isindependently an optionally substituted group selected from C₁₋₆aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partiallyunsaturated monocyclic carbocyclic ring; a 3-7 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, phosphorous,silicon and sulfur; or a 5-6 membered monocyclic heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; a 5-8 memberedsaturated or partially unsaturated bridged bicyclic ring having 0-3heteroatoms independently selected from nitrogen, oxygen, and sulfur; a6-10 membered saturated or partially unsaturated spirocyclic ring having0-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur; or a 6-11 membered saturated or partially unsaturated bicyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur.

In some embodiments, each instance of R^(C) is oxo, halogen, —CN, —NO₂,—OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R, —C(O)OR,—C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,—N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)NR₂, —N(R)S(O)₂NR₂, —N(R)S(O)₂R,—N═S(O)R₂, —S(NR)(O)R, —N(R)S(O)R, —N(R)CN, —P(O)(R)NR₂, —P(O)(R)OR or—P(O)R₂.

In some embodiments, each instance of R^(C) is an optionally substitutedgroup selected from C₁₋₆ aliphatic; phenyl; naphthalenyl; a 3-7 memberedsaturated or partially unsaturated monocyclic carbocyclic ring; a 3-7membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen,phosphorous, silicon and sulfur; or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur; a5-8 membered saturated or partially unsaturated bridged bicyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur; a 6-10 membered saturated or partially unsaturated spirocyclicring having 0-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur; or a 6-11 membered saturated or partiallyunsaturated bicyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R^(C) is a 6-11 membered saturated or partiallyunsaturated spirocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur which is substituted with rinstances of R and s instances of R^(D).

In some embodiments, R^(C) is a 6-11 membered saturated or partiallyunsaturated bicyclic heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur which issubstituted with r instances of R and s instances of R^(D).

In some embodiments, R^(C) is methyl, oxo, fluoro or methoxy.

In some embodiments, R^(C) is

In some embodiments, R^(C) is —CHF₂ or chloro.

In some embodiments, R^(C) is

In some embodiments, R^(C) is

In some embodiments, each instance of R^(C) is selected from thosedepicted in Table 1, below.

As defined generally above, each instance of R^(D) is independently oxo,halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,—S(O)NR₂, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,—N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)NR₂,—N(R)S(O)₂NR₂, —N(R)S(O)₂R, —N═S(O)R₂, —S(NR)(O)R, —N(R)S(O)R, —N(R)CN,—P(O)(R)NR₂, —P(O)(R)OR or —P(O)R₂.

In some embodiments, R^(D) is oxo, halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,—N(R)C(NR)NR₂, —N(R)NR₂, —N(R)S(O)₂NR₂, —N(R)S(O)₂R, —N═S(O)R₂,—S(NR)(O)R, —N(R)S(O)R, —N(R)CN, —P(O)(R)NR₂, —P(O)(R)OR or —P(O)R₂.

In some embodiments, R^(D) is hydroxy, fluoro, or methoxy.

In some embodiments, R^(D) is

In some embodiments, R^(D) is oxo.

In some embodiments, R^(D) is

In some embodiments, R^(D) is selected from those depicted in Table 1,below.

As defined generally above, each R is independently hydrogen, or anoptionally substituted group selected from C₁₋₆ aliphatic; phenyl;naphthalenyl; a 3-7 membered saturated or partially unsaturatedmonocyclic carbocyclic ring; a 3-7 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; a 5-6 memberedmonocyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; a 7-12 membered saturated or partially unsaturatedbicyclic heterocyclic ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partiallyunsaturated bridged bicyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated orpartially unsaturated spirocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; a 6-11membered saturated or partially unsaturated bicyclic carbocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur; or:

two R groups on the same nitrogen are taken together with the nitrogento form an optionally substituted 4-7 membered monocyclic saturated,partially unsaturated, or heteroaryl ring having, in addition to thenitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen,and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur; a7-12 membered saturated or partially unsaturated bicyclic heterocyclicring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

In some embodiments, R is methyl. In some embodiments, R is

In some embodiments, R is ethyl.

In some embodiments, R is

In some embodiments, R is selected from those depicted in Table 1,below.

As defined generally above, each hydrogen bound to carbon can beoptionally and independently replaced by deuterium.

In some embodiments, a hydrogen bound to carbon is replaced bydeuterium.

As defined generally above, m is 0, 1, or 2.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2.

In some embodiments, m is selected from those depicted in Table 1,below.

As defined generally above, q is 0, 1, 2, 3, or 4. In some embodiments,q is 0. In some embodiments, q is 1, 2, 3, or 4. In some embodiments, qis 1. In some embodiments, q is 2. In some embodiments, q is 3. In someembodiments, q is 4.

In some embodiments, q is 1, 2, or 3. In some embodiments, q is 1 or 2.

In some embodiments, q is selected from those depicted in Table 1,below.

As defined generally above, r is 0, 1, 2, 3, or 4. In some embodiments,r is 0. In some embodiments, r is 1, 2, 3, or 4. In some embodiments, ris 1. In some embodiments, r is 2. In some embodiments, r is 3. In someembodiments, r is 4.

In some embodiments, r is 1 or 2. In some embodiments, r is 2 or 3. Insome embodiments, r is 2, 3, or 4.

In some embodiments, r is selected from those depicted in Table 1,below.

As defined generally above, s is 0, 1, 2, 3, or 4. In some embodiments,s is 0. In some embodiments, s is 1, 2, 3, or 4. In some embodiments, sis 1. In some embodiments, s is 2. In some embodiments, s is 3. In someembodiments, s is 4.

In some embodiments, s is 1 or 2. In some embodiments, s is 2 or 3. Insome embodiments, s is 2, 3, or 4.

In some embodiments, s is selected from those depicted in Table 1,below.

In some embodiments, the present invention provides a compound offormula II:

or a pharmaceutically acceptable salt thereof, wherein each of R¹ andR², is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides a compound offormula III:

or a pharmaceutically acceptable salt thereof, wherein each of R¹ andR², is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides a compound offormula IV:

or a pharmaceutically acceptable salt thereof, wherein each of R² andR^(C) is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula V:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²and X, is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula VI:

or a pharmaceutically acceptable salt thereof, wherein each of R¹ andR², is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides a compound offormula VII:

or a pharmaceutically acceptable salt thereof, wherein each of R² andR^(C) is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula XI-a, or XI-b:

or a pharmaceutically acceptable salt thereof, wherein each of ¹R,R^(C), X, and q, is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula XII-a or XII-b:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R^(C)and q, is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula XIII-a or XIII-b:

or a pharmaceutically acceptable salt thereof, wherein each of R^(C) andq is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides a compound offormula XIV-a or XIV-b:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(C), X, and q, is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula XV-a or XV-b:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R^(C)and q is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula XVI-a or XVI-b:

or a pharmaceutically acceptable salt thereof, wherein each of R^(C) andq is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides a compound offormula XVII-a or XVII-b:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(C), X, and q, is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula XVIII-a or XVIII-b:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R^(C)and q is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula XIX-a or XIX-b:

or a pharmaceutically acceptable salt thereof, wherein each of R^(C) andq is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides a compound offormula XX-a or XX-b:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(C), X, and q, is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula XXI-a or XXI-b:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(C), X, and q, is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula XXII-a or XXII-b:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(C), X, and q, is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula XXIII-a or XXIII-b:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(C), X, and q, is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula XXIV-a or XXIV-b:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(C), X, and q, is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula XXV-a or XXV-b:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(C), X, and q, is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula XXVI-a or XXVI-b:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(C), X, and q, is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula XXVII-a or XXVII-b:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(C), X, and q, is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula XXVIII-a or XXVIII-b:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(C), X, and q, is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula XXIX-a or XXIX-b:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(C), X, and q, is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula XXX-a or XXX-b:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(C), X, and q, is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula XXXI-a or XXXI-b:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(C), X, and q, is as defined above and described in embodimentsherein, both singly and in combination.

Exemplary compounds of the invention are set forth in Table 1, below.

TABLE 1 Selected Compounds # Structure I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

I-154

I-155

I-156

I-157

I-158

I-159

I-160

I-161

I-162

I-163

I-164

I-165

I-166

I-167

I-168

I-169

I-170

I-171

I-172

I-173

I-174

I-175

I-176

I-177

I-178

I-179

I-180

I-181

I-182

I-183

I-184

I-185

I-186

I-187

I-188

I-189

I-190

I-191

I-192

I-193

I-194

I-195

I-196

I-197

I-198

I-199

I-200

I-201

I-202

I-203

I-204

I-205

I-206

I-207

I-208

I-209

I-210

I-211

I-212

I-213

I-214

I-215

I-216

I-217

I-218

I-219

I-220

I-221

I-222

I-223

I-224

I-225

I-226

I-227

I-228

I-229

I-230

I-231

I-232

I-233

I-234

I-235

I-236

I-237

I-238

I-239

I-240

I-241

I-242

I-243

I-244

I-245

I-246

I-247

I-248

I-249

I-250

I-251

I-252

I-253

I-254

I-255

I-256

I-257

I-258

I-259

I-260

I-261

I-262

I-263

I-264

I-265

I-266

I-267

I-268

I-269

I-270

I-271

I-272

I-273

I-274

I-275

I-276

I-278

I-279

I-280

I-281

I-282

I-283

I-284

I-285

I-286

I-287

I-288

I-289

I-290

I-291

I-292

I-293

I-294

I-295

I-296

I-297

I-298

I-299

I-300

I-301

I-302

I-303

I-304

I-305

I-306

I-307

I-308

I-309

I-310

I-311

I-312

I-313

I-314

I-315

I-316

I-317

I-318

I-319

I-320

I-321

I-322

I-323

I-324

I-325

I-326

I-327

I-328

I-329

I-330

I-331

I-332

I-333

I-334

I-335

I-336

I-338

I-339

I-340

I-341

I-342

I-343

I-344

I-345

I-346

I-347

I-348

I-349

I-350

I-351

I-352

I-353

I-354

I-355

I-356

I-357

I-358

I-359

I-360

I-361

I-362

I-363

I-364

I-365

I-366

I-367

I-368

I-369

I-370

I-371

I-372

I-373

I-374

I-375

I-376

I-377

I-378

I-379

I-380

I-381

I-382

I-383

I-384

I-385

I-386

I-387

I-388

I-389

I-390

I-391

I-392

I-393

I-394

I-395

I-396

I-397

I-398

I-399

I-400

I-401

I-402

I-403

I-404

I-405

I-406

I-407

I-408

I-411

I-412

I-413

I-414

I-415

I-416

I-417

I-418

I-419

I-420

I-421

I-422

I-423

I-424

I-425

I-426

I-427

I-428

I-429

I-430

I-431

I-432

I-433

I-434

I-435

I-436

I-437

I-438

I-439

I-440

I-441

I-442

I-443

I-444

I-445

I-446

I-447

I-448

I-449

I-450

I-451

I-452

I-453

I-454

I-455

I-456

I-457

I-458

I-459

I-460

I-461

I-462

I-463

I-464

I-465

I-467

I-468

I-469

I-470

I-471

I-472

I-473

I-474

I-475

I-476

I-477

I-478

I-479

I-480

I-481

I-482

I-483

I-484

I-485

I-486

I-487

I-488

I-489

I-490

I-491

I-492

I-493

I-494

I-495

I-496

I-497

I-498

I-499

I-500

I-501

I-502

I-503

I-504

I-505

I-506a

I-506

I-507

I-508

I-509

I-510

I-511

I-512

I-513

I-514

I-515

I-516

I-517

I-518

I-519

I-520

I-521

I-522

I-523

I-524

I-525

I-526

I-527

I-528

I-529

I-530

I-531

I-532

I-533

I-534

I-535

I-536

I-537

I-538

I-539

I-540

I-541

I-542

I-543

I-544

I-545

I-546

I-547

I-548

I-549

I-550

I-551

I-552

I-553

I-554

I-555

I-556

I-557

I-558

I-559

I-560

I-561

I-562

I-563

I-564

I-565

I-566

I-567

I-568

I-569

I-570

I-571

I-572

I-573

I-574

I-575

I-576

I-577

I-578

I-579

I-580

I-581

I-582

I-583

I-584

I-585

I-586

I-587

I-588

I-589

I-590

I-591

I-592

I-593

I-594

I-595

I-596

I-597

I-598

I-599

I-600

I-601

I-602

I-603

I-604

I-605

I-606

I-607

I-608

I-609

I-610

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I-830

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TZ,1/38

In some embodiments, the present invention provides a compound set forthin Table 1, above, or a pharmaceutically acceptable salt thereof. Insome embodiments, the present invention provides a compound set forth inTable 1, above. In some embodiments, the present invention provides apharmaceutical composition comprising a compound set forth in Table 1above, or a pharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier, excipient, or diluent.

In some embodiments, the present invention provides a compound offormula I as defined above, or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition comprising a compound offormula I as defined above, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier, adjuvant, or vehiclefor use as a medicament.

In some embodiments, the invention also provides compounds of formula Idescribed herein or pharmaceutical compositions described herein for usein a method for inhibiting HPK1 as described herein, in a method forenhancing an immune response in a subject in need thereof as describedherein and/or in a method for treating a HPK1-dependent disorder asdescribed herein.

In some embodiments, the invention also provides compounds of formula Idescribed herein or pharmaceutical compositions described herein for usein a method for inhibiting HPK1 as described herein.

In some embodiments, the invention also provides compounds of formula Idescribed herein or pharmaceutical compositions described herein for usein a method for enhancing an immune response in a subject in needthereof as described herein.

In some embodiments, the invention also provides compounds of formula Idescribed herein or pharmaceutical compositions described herein for usein a method for treating a HPK1-dependent disorder as described herein.

In some embodiments, the invention also provides the use of a compoundof formula I described herein or a pharmaceutical composition describedherein for the manufacture of a medicament for inhibiting HPK1, amedicament for enhancing an immune response in a subject in need thereofand/or a medicament for treating a HPK1-dependent disorder.

In some embodiments, the invention also provides the use of a compoundof formula I described herein or a pharmaceutical composition describedherein for the manufacture of a medicament for inhibiting HPK1.

In some embodiments, the invention also provides the use of a compoundof formula I described herein or a pharmaceutical composition describedherein for the manufacture of a medicament for enhancing an immuneresponse in a subject in need thereof.

In some embodiments, the invention also provides the use of a compoundof formula I described herein or a pharmaceutical composition describedherein for the manufacture of a medicament treating a HPK1-dependentdisorder.

In some embodiments, the invention also provides the use of compounds offormula I described herein or pharmaceutical compositions describedherein in a method for inhibiting HPK1 as described herein, in a methodfor enhancing an immune response in a subject in need thereof asdescribed herein and/or in a method for treating a HPK1-dependentdisorder as described herein.

In some embodiments, the invention also provides the use of compounds offormula I described herein or pharmaceutical compositions describedherein in a method for inhibiting HPK1 as described herein.

In some embodiments, the invention also provides the use of compounds offormula I described herein or pharmaceutical compositions describedherein in a method for enhancing an immune response in a subject in needthereof as described herein.

In some embodiments, the invention also provides the use of compounds offormula I described herein or pharmaceutical compositions describedherein in a method for treating a HPK1-dependent disorder as describedherein.

4. General Methods of Providing the Present Compounds

The compounds of this invention may be prepared or isolated in generalby synthetic and/or semi-synthetic methods known to those skilled in theart for analogous compounds and by methods described in detail in theExamples, herein.

5. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably inhibit HPK1, or a mutant thereof,in a biological sample or in a patient. In certain embodiments, theamount of compound in compositions of this invention is such that iseffective to measurably inhibit HPK1, or a mutant thereof, in abiological sample or in a patient. In certain embodiments, a compositionof this invention is formulated for administration to a patient in needof such composition. In some embodiments, a composition of thisinvention is formulated for oral administration to a patient.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof.

As used herein, the term “inhibitorily active metabolite or residuethereof” means that a metabolite or residue thereof is also an inhibitorof HPK1, or a mutant thereof.

The subject matter disclosed herein includes prodrugs, metabolites,derivatives, and pharmaceutically acceptable salts of compounds of theinvention. Metabolites include compounds produced by a processcomprising contacting a compound of the invention with a mammal for aperiod of time sufficient to yield a metabolic product thereof. If thecompound of the invention is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an inorganic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,methanesulfonic acid, phosphoric acid and the like, or with an organicacid, such as acetic acid, maleic acid, succinic acid, mandelic acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, a pyranosidyl acid, such as glucuronic acid orgalacturonic acid, an alpha hydroxy acid, such as citric acid ortartaric acid, an amino acid, such as aspartic acid or glutamic acid, anaromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid,such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. Ifthe compound of the invention is an acid, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method, for example,treatment of the free acid with an inorganic or organic base, such as anamine (primary, secondary or tertiary), an alkali metal hydroxide oralkaline earth metal hydroxide, or the like. Illustrative examples ofsuitable salts include, but are not limited to, organic salts derivedfrom amino acids, such as glycine and arginine, ammonia, primary,secondary, and tertiary amines, and cyclic amines, such as piperidine,morpholine and piperazine, and inorganic salts derived from sodium,calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminumand lithium.

A compound of the invention can be in the form of a “prodrug,” whichincludes compounds with moieties which can be metabolized in vivo.Generally, the prodrugs are metabolized in vivo by esterases or by othermechanisms to active drugs. Examples of prodrugs and their uses are wellknown in the art (See, e.g., Berge et al. (1977) “Pharmaceutical Salts”,J. Pharm. Sci. 66:1-19). The prodrugs can be prepared in situ during thefinal isolation and purification of the compounds, or by separatelyreacting the purified compound in its free acid form or hydroxyl with asuitable esterifying agent. Hydroxyl groups can be converted into estersvia treatment with a carboxylic acid. Examples of prodrug moietiesinclude substituted and unsubstituted, branch or unbranched lower alkylester moieties, (e.g., propionic acid esters), lower alkenyl esters,di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethylester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester),acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters(phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester),substituted (e.g., with methyl, halo, or methoxy substituents) aryl andaryl-lower alkyl esters, amides, lower-alkyl amides, di-lower alkylamides, and hydroxy amides. Prodrugs which are converted to active formsthrough other mechanisms in vivo are also included. In aspects, thecompounds of the invention are prodrugs of any of the formulae herein.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of theinhibitor can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

The compounds and compositions described herein are generally useful forthe inhibition of kinase activity of one or more enzymes. In someembodiments the kinase inhibited by the compounds and methods of theinvention is HPK1.

The presently disclosed compounds find use in inhibiting the activity ofthe enzyme HPK1. HPK1 is a member of the germinal center kinasesubfamily of Ste20-related serine/threonine kinases. HPK1 functions as aMAP4K by phosphorylating and activating MAP3K proteins, including MEKK1,MLK3 and TAK1, leading to the activation of the MAPK Jnk.

In one embodiment, the subject matter disclosed herein is directed to amethod of inhibiting HPK1, the method comprising contacting HPK1 with aneffective amount of a compound of the invention or a pharmaceuticalcomposition described herein.

In certain embodiments, the subject matter disclosed herein is directedto a method for enhancing an immune response in a subject in needthereof, wherein the method comprises administering to the subject aneffective amount of a compound of the invention or a pharmaceuticalcomposition described herein. In certain aspects of this embodiment, theT cells in the subject have at least one of enhanced priming, enhancedactivation, enhanced migration, enhanced proliferation, enhancedsurvival, and enhanced cytolytic activity relative to prior to theadministration of the compound or pharmaceutical composition. In certainaspects of this embodiment, the T cell activation is characterized by anelevated frequency of γ-IFN+CD8 T cells or enhanced levels of IL-2 orgranzyme B production by T cells relative to prior to administration ofthe compound or pharmaceutical composition. In certain aspects of thisembodiment, the number of T cells is elevated relative to prior toadministration of the compound or pharmaceutical composition. In certainaspects of this embodiment, the T cell is an antigen-specific CD8 Tcell. In certain aspects of this embodiment, the antigen presentingcells in the subject have enhanced maturation and activation relativeprior to the administration of the compound or pharmaceuticalcomposition. In certain aspects of this embodiment, the antigenpresenting cells are dendritic cells. In certain aspects of thisembodiment, the maturation of the antigen presenting cells ischaracterized by increased frequency of CD83+ dendritic cells. Incertain aspects of this embodiment, the activation of the antigenpresenting cells is characterized by elevated expression of CD80 andCD86 on dendritic cells.

The presently disclosed compounds bind directly to HPK1 and inhibit itskinase activity. In some embodiments, the presently disclosed compoundsreduce, inhibit, or otherwise diminish the HPK1-mediated phosphorylationof SLP76 and/or Gads.

The presently disclosed compounds may or may not be a specific HPK1antagonist. A specific HPK1 antagonist reduces the biological activityof HPK1 by an amount that is statistically greater than the inhibitoryeffect of the antagonist on any other protein (e.g., otherserine/threonine kinases). In certain embodiments, the presentlydisclosed compounds specifically inhibit the serine/threonine kinaseactivity of HPK1. In some of these embodiments, the IC₅₀ of the HPK1antagonist for HPK1 is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,10%, 0.1%, 0.01%, 0.001%, or less of the IC₅₀ of the HPK1 antagonist foranother serine/threonine kinase or other type of kinase (e.g., tyrosinekinase).

The presently disclosed compounds can be used in a method for inhibitingHPK1. Such methods comprise contacting HPK1 with an effective amount ofa presently disclosed compound. By “contact” is intended bringing thecompound within close enough proximity to an isolated HPK1 enzyme or acell expressing HPK1 (e.g., T cell, B cell, dendritic cell) such thatthe compound is able to bind to and inhibit the activity of HPK1. Thecompound can be contacted with HPK1 in vitro or in vivo viaadministration of the compound to a subject.

Any method known in the art to measure the kinase activity of HPK1 maybe used to determine if HPK1 has been inhibited, including in vitrokinase assays, immunoblots with antibodies specific for phosphorylatedtargets of HPK1, such as SLP76 and Gads, or the measurement of adownstream biological effect of HPK1 kinase activity, such as therecruitment of 14-3-3 proteins to phosphorylated SLP7 and Gads, releaseof the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, or Tor B cell activation.

The presently disclosed compounds can be used to treat a HPK1-dependentdisorder. As used herein, a “HPK1-dependent disorder” is a pathologicalcondition in which HPK1 activity is necessary for the genesis ormaintenance of the pathological condition. In some embodiments, theHPK1-dependent disorder is cancer.

The presently disclosed compounds also find use in enhancing an immuneresponse in a subject in need thereof. Such methods compriseadministering an effective amount of a compound of the invention.

As used herein, “enhancing an immune response” refers to an improvementin any immunogenic response to an antigen. Non-limiting examples ofimprovements in an immunogenic response to an antigen include enhancedmaturation or migration of dendritic cells, enhanced activation of Tcells (e.g., CD4 T cells, CD8 T cells), enhanced T cell (e.g., CD4 Tcell, CD8 T cell) proliferation, enhanced B cell proliferation,increased survival of T cells and/or B cells, improved antigenpresentation by antigen presenting cells (e.g., dendritic cells),improved antigen clearance, increase in production of cytokines by Tcells (e.g., interleukin-2), increased resistance to prostaglandinE2-induced immune suppression, and enhanced priming and/or cytolyticactivity of CD8 T cells.

In some embodiments, the CD8 T cells in the subject have enhancedpriming, activation, proliferation and/or cytolytic activity relative toprior to the administration of the compound of the invention or apharmaceutically acceptable salt, prodrug, metabolite, or derivativethereof. In some embodiments, the CD8 T cell priming is characterized byelevated CD44 expression and/or enhanced cytolytic activity in CD8 Tcells. In some embodiments, the CD8 T cell activation is characterizedby an elevated frequency of γ-IFN⁺ CD8 T cells. In some embodiments, theCD8 T cell is an antigen-specific T-cell.

In some embodiments, the antigen presenting cells in the subject haveenhanced maturation and activation relative to prior to theadministration of the compound of the invention or a pharmaceuticallyacceptable salt, prodrug, metabolite, or derivative thereof. In someembodiments, the antigen presenting cells are dendritic cells. In someembodiments, the maturation of the antigen presenting cells ischaracterized by an increased frequency of CD83⁺ dendritic cells. Insome embodiments, the activation of the antigen presenting cells ischaracterized by elevated expression of CD80 and CD86 on dendriticcells.

In some embodiments, the serum levels of cytokine IL-10 and/or chemokineIL-8, a human homolog of murine KC, in the subject are reduced relativeto prior to the administration of the compound of Formula I or Ia or apharmaceutically acceptable salt, prodrug, metabolite, or derivativethereof.

Engagement of the TCR leads to HPK1 activation, which functions as anegative regulator of TCR-induced AP-1 response pathway. It is believedthat HPK1 negatively regulates T cell activation by reducing thepersistence of signaling microclusters by phosphorylating SLP76 atSer376 (Di Bartolo et al. (2007) JEM 204:681-691) and Gads at Thr254,which leads to the recruitment of 14-3-3 proteins that bind to thephosphorylated SLP76 and Gads, releasing the SLP76-Gads-14-3-3 complexfrom LAT-containing microclusters, which leads to T cell dysfunction,including anergy and exhaustion (Lasserre et al. (2011) J Cell Biol195(5):839-853).

In some embodiments, administration of a compound of the invention or apharmaceutically acceptable salt, prodrug, metabolite, or derivativethereof to a subject results in an enhancement of T cell function.

Accordingly, the presently disclosed compounds of the invention orpharmaceutically acceptable salts, prodrugs, metabolites, or derivativesthereof are useful in treating T cell dysfunctional disorders. A “T celldysfunctional disorder” is a disorder or condition of T cellscharacterized by decreased responsiveness to antigenic stimulation. In aparticular embodiment, a T cell dysfunctional disorder is a disorderthat is specifically associated with increased kinase activity of HPK1.In another embodiment, a T cell dysfunctional disorder is one in which Tcells are anergic or have decreased ability to secrete cytokines,proliferate, or execute cytolytic activity. In a specific aspect, thedecreased responsiveness results in ineffective control of a pathogen ortumor expressing an immunogen. Examples of T cell dysfunctionaldisorders characterized by T-cell dysfunction include unresolved acuteinfection, chronic infection and tumor immunity.

Thus, the presently disclosed compounds can be used in treatingconditions where enhanced immunogenicity is desired, such as increasingtumor immunogenicity for the treatment of cancer.

The term “dysfunction” in the context of immune dysfunction, refers to astate of reduced immune responsiveness to antigenic stimulation. Theterm includes the common elements of both exhaustion and/or anergy inwhich antigen recognition may occur, but the ensuing immune response isineffective to control infection or tumor growth.

The term “dysfunctional”, as used herein, also includes refractory orunresponsive to antigen recognition, specifically, impaired capacity totranslate antigen recognition into downstream T-cell effector functions,such as proliferation, cytokine production (e.g., IL-2, y-IFN) and/ortarget cell killing.

The term “anergy” refers to the state of unresponsiveness to antigenstimulation resulting from incomplete or insufficient signals deliveredthrough the T-cell receptor (e.g. increase in intracellular Ca′ in theabsence of ras-activation). T cell anergy can also result uponstimulation with antigen in the absence of co-stimulation, resulting inthe cell becoming refractory to subsequent activation by the antigeneven in the context of costimulation. The unresponsive state can oftenbe overridden by the presence of Interleukin-2. Anergic T-cells do notundergo clonal expansion and/or acquire effector functions.

The term “exhaustion” refers to T cell exhaustion as a state of T celldysfunction that arises from sustained TCR signaling that occurs duringmany chronic infections and cancer. It is distinguished from anergy inthat it arises not through incomplete or deficient signaling, but fromsustained signaling. It is defined by poor effector function, sustainedexpression of inhibitory receptors and a transcriptional state distinctfrom that of functional effector or memory T cells. Exhaustion preventsoptimal control of infection and tumors. Exhaustion can result from bothextrinsic negative regulatory pathways (e.g., immunoregulatorycytokines) as well as cell intrinsic negative regulatory (costimulatory)pathways (PD-1, B7-H3, B7-H4, etc.).

“Immunogenecity” refers to the ability of a particular substance toprovoke an immune response. Tumors are immunogenic and enhancing tumorimmunogenicity aids in the clearance of the tumor cells by the immuneresponse.

“Enhancing T cell function” means to induce, cause or stimulate a T cellto have a sustained or amplified biological function, or renew orreactivate exhausted or inactive T cells. Examples of enhancing T cellfunction include: increased secretion of cytokines (e.g., y-interferon,IL-2, IL-12, and TNFα), increased proliferation, increased antigenresponsiveness (e.g., viral, pathogen, or tumor clearance) relative tosuch levels before the intervention, and increased effector granuleproduction by CD8 T cells, such as granzyme B. In one embodiment, thelevel of enhancement is as least 50%, alternatively 60%, 70%, 80%, 90%,100%, 120%, 150%, 200%. The manner of measuring this enhancement isknown to one of ordinary skill in the art.

“Tumor immunity” refers to the process in which tumors evade immunerecognition and clearance. Thus, as a therapeutic concept, tumorimmunity is “treated” when such evasion is attenuated, and the tumorsare recognized and attacked by the immune system. Examples of tumorrecognition include tumor binding, tumor shrinkage and tumor clearance.

The present disclosure provides methods of modulating (e.g., inhibiting)HPK1 activity, said method comprising administering to a patient acompound provided herein, or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein is a method for treating of cancer in asubject in need thereof comprising administering to the subject aneffective amount of a compound of the invention or a pharmaceuticallyacceptable salt, prodrug, metabolite, or derivative thereof.

In the methods described herein, a compound of the invention or apharmaceutical composition thereof is administered to a subject that hascancer.

In certain embodiments, the subject matter disclosed herein is directedto a method for treating a HPK1-dependent disorder, the methodcomprising administering to a subject in need thereof an effectiveamount of a compound of the invention or a pharmaceutical compositiondescribed herein. In certain aspects of this embodiment, theHPK1-dependent disorder is a cancer. In certain aspects of thisembodiment, the cancer comprises at least one cancer selected from thegroup consisting of colorectal cancer, melanoma, non-small cell lungcancer, ovarian cancer, breast cancer, pancreatic cancer, ahematological malignancy, and a renal cell carcinoma. In certain aspectsof this embodiment, the cancer has elevated levels of T-cellinfiltration. In certain aspects of this embodiment, the cancer cells inthe subject selectively have elevated expression of MHC class I antigenexpression relative to prior to the administration of the compound orcomposition.

In some embodiments, the subject matter disclosed herein is directed toa method for treatment of chronic viral infections. In some embodiments,the subject matter disclosed herein is directed to the use of an HPK1inhibitor as an adjuvant treatment for increasing the efficacy ofvaccination.

In some embodiments, the invention provides a pharmaceutical compositioncomprising an effective amount of a compound of the invention, or apharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof,and a pharmaceutically acceptable carrier.

In certain aspects, the invention provides a method of treating cellproliferation disorders, including cancers, benign papillomatosis,gestational trophoblastic diseases, and benign neoplastic diseases, suchas skin papilloma (warts) and genital papilloma.

In one aspect, the invention provides a method of treating a cellproliferation disorder in a subject, comprising administering atherapeutically effective amount of a compound of the invention, or apharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof,to the subject.

In certain embodiments, the cell proliferation disorder is cancer.

Examples of cancers that are treatable using the compounds of thepresent disclosure include, but are not limited to, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal region, stomach cancer, testicular cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, endometrial cancer, carcinoma of the cervix, carcinoma ofthe vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin'slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors ofchildhood, lymphocytic lymphoma, cancer of the bladder, cancer of thekidney or urethra, carcinoma of the renal pelvis, neoplasm of thecentral nervous system (CNS), primary CNS lymphoma, tumor angiogenesis,spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi'ssarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to, solid tumors(e.g., prostate cancer, colon cancer, esophageal cancer, endometrialcancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancersof the head and neck, thyroid cancer, glioblastoma, sarcoma, bladdercancer, etc.), hematological cancers (e.g., lymphoma, leukemia such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed orrefractory NHL and recurrent follicular), Hodgkin lymphoma or multiplemyeloma) and combinations of said cancers.

In certain embodiments, the cancer is brain cancer, leukemia, skincancer, prostate cancer, thyroid cancer, colon cancer, lung cancer orsarcoma. In another embodiment the cancer is selected from the groupconsisting of glioma, glioblastoma multiforme, paraganglioma,suprantentorial primordial neuroectodermal tumors, acute myeloidleukemia, myelodysplastic syndrome, chronic myelogenous leukemia,melanoma, breast, prostate, thyroid, colon, lung, centralchondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma,and cholangiocarcinoma.

In certain embodiments, the cancer is selected from brain and spinalcancers, cancers of the head and neck, leukemia and cancers of theblood, skin cancers, cancers of the reproductive system, cancers of thegastrointestinal system, liver and bile duct cancers, kidney and bladdercancers, bone cancers, lung cancers, malignant mesothelioma, sarcomas,lymphomas, glandular cancers, thyroid cancers, heart tumors, germ celltumors, malignant neuroendocrine (carcinoid) tumors, midline tractcancers, and cancers of unknown primary (cancers in which a metastasizedcancer is found but the original cancer site is not known). Inparticular embodiments, the cancer is present in an adult patient; inadditional embodiments, the cancer is present in a pediatric patient. Inparticular embodiments, the cancer is AIDS-related.

In a further embodiment, the cancer is selected from brain and spinalcancers. In particular embodiments, the cancer is selected from thegroup consisting of anaplastic astrocytomas, glioblastomas,astrocytomas, and estheosioneuroblastomas (olfactory blastomas). Inparticular embodiments, the brain cancer is selected from the groupconsisting of astrocytic tumor (e.g., pilocytic astrocytoma,subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphicxanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cellglioblastoma, glioblastoma, secondary glioblastoma, primary adultglioblastoma, and primary pediatric glioblastoma), oligodendroglialtumor (e.g., oligodendroglioma, and anaplastic oligodendroglioma),oligoastrocytic tumor (e.g., oligoastrocytoma, and anaplasticoligoastrocytoma), ependymoma (e.g., myxopapillary ependymoma, andanaplastic ependymoma); medulloblastoma, primitive neuroectodermaltumor, schwannoma, meningioma, atypical meningioma, anaplasticmeningioma, pituitary adenoma, brain stem glioma, cerebellarastrocytoma, cerebral astorcytoma/malignant glioma, visual pathway andhypothalmic glioma, and primary central nervous system lymphoma. Inspecific instances of these embodiments, the brain cancer is selectedfrom the group consisting of glioma, glioblastoma multiforme,paraganglioma, and suprantentorial primordial neuroectodermal tumors(sPNET).

In specific embodiments, the cancer is selected from cancers of the headand neck, including nasopharyngeal cancers, nasal cavity and paranasalsinus cancers, hypopharyngeal cancers, oral cavity cancers (e.g.,squamous cell carcinomas, lymphomas, and sarcomas), lip cancers,oropharyngeal cancers, salivary gland tumors, cancers of the larynx(e.g., laryngeal squamous cell carcinomas, rhabdomyosarcomas), andcancers of the eye or ocular cancers. In particular embodiments, theocular cancer is selected from the group consisting of intraocularmelanoma and retinoblastoma.

In specific embodiments, the cancer is selected from leukemia andcancers of the blood. In particular embodiments, the cancer is selectedfrom the group consisting of myeloproliferative neoplasms,myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms,acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronicmyelogenous leukemia (CML), myeloproliferative neoplasm (MPN), post-MPNAML, post-MDS AML, del(5q)-associated high risk MDS or AML, blast-phasechronic myelogenous leukemia, angioimmunoblastic lymphoma, acutelymphoblastic leukemia, Langerans cell histiocytosis, hairy cellleukemia, and plasma cell neoplasms including plasmacytomas and multiplemyelomas. Leukemias referenced herein may be acute or chronic.

In specific embodiments, the cancer is selected from skin cancers. Inparticular embodiments, the skin cancer is selected from the groupconsisting of melanoma, squamous cell cancers, and basal cell cancers.

In specific embodiments, the cancer is selected from cancers of thereproductive system. In particular embodiments, the cancer is selectedfrom the group consisting of breast cancers, cervical cancers, vaginalcancers, ovarian cancers, prostate cancers, penile cancers, andtesticular cancers. In specific instances of these embodiments, thecancer is a breast cancer selected from the group consisting of ductalcarcinomas and phyllodes tumors. In specific instances of theseembodiments, the breast cancer may be male breast cancer or femalebreast cancer. In specific instances of these embodiments, the cancer isa cervical cancer selected from the group consisting of squamous cellcarcinomas and adenocarcinomas. In specific instances of theseembodiments, the cancer is an ovarian cancer selected from the groupconsisting of epithelial cancers.

In specific embodiments, the cancer is selected from cancers of thegastrointestinal system. In particular embodiments, the cancer isselected from the group consisting of esophageal cancers, gastriccancers (also known as stomach cancers), gastrointestinal carcinoidtumors, pancreatic cancers, gallbladder cancers, colorectal cancers, andanal cancer. In instances of these embodiments, the cancer is selectedfrom the group consisting of esophageal squamous cell carcinomas,esophageal adenocarcinomas, gastric adenocarcinomas, gastrointestinalcarcinoid tumors, gastrointestinal stromal tumors, gastric lymphomas,gastrointestinal lymphomas, solid pseudopapillary tumors of thepancreas, pancreatoblastoma, islet cell tumors, pancreatic carcinomasincluding acinar cell carcinomas and ductal adenocarcinomas, gallbladderadenocarcinomas, colorectal adenocarcinomas, and anal squamous cellcarcinomas.

In specific embodiments, the cancer is selected from liver and bile ductcancers. In particular embodiments, the cancer is liver cancer(hepatocellular carcinoma). In particular embodiments, the cancer isbile duct cancer (cholangiocarcinoma); in instances of theseembodiments, the bile duct cancer is selected from the group consistingof intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.

In specific embodiments, the cancer is selected from kidney and bladdercancers. In particular embodiments, the cancer is a kidney cancerselected from the group consisting of renal cell cancer, Wilms tumors,and transitional cell cancers. In particular embodiments, the cancer isa bladder cancer selected from the group consisting of urethelialcarcinoma (a transitional cell carcinoma), squamous cell carcinomas, andadenocarcinomas.

In specific embodiments, the cancer is selected from bone cancers. Inparticular embodiments, the bone cancer is selected from the groupconsisting of osteosarcoma, malignant fibrous histiocytoma of bone,Ewing sarcoma, and chordoma.

In specific embodiments, the cancer is selected from lung cancers. Inparticular embodiments, the lung cancer is selected from the groupconsisting of non-small cell lung cancer, small cell lung cancers,bronchial tumors, and pleuropulmonary blastomas.

In specific embodiments, the cancer is selected from malignantmesothelioma. In particular embodiments, the cancer is selected from thegroup consisting of epithelial mesothelioma and sarcomatoids.

In specific embodiments, the cancer is selected from sarcomas. Inparticular embodiments, the sarcoma is selected from the groupconsisting of central chondrosarcoma, central and periosteal chondroma,fibrosarcoma, clear cell sarcoma of tendon sheaths, and Kaposi'ssarcoma.

In specific embodiments, the cancer is selected from lymphomas. Inparticular embodiments, the cancer is selected from the group consistingof Hodgkin lymphoma (e.g., Reed-Sternberg cells), non-Hodgkin lymphoma(e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosisfungoides, Sezary syndrome, primary central nervous system lymphoma),cutaneous T-cell lymphomas, and primary central nervous systemlymphomas.

In specific embodiments, the cancer is selected from glandular cancers.In particular embodiments, the cancer is selected from the groupconsisting of adrenocortical cancer, pheochromocytomas, paragangliomas,pituitary tumors, thymoma, and thymic carcinomas.

In specific embodiments, the cancer is selected from thyroid cancers. Inparticular embodiments, the thyroid cancer is selected from the groupconsisting of medullary thyroid carcinomas, papillary thyroidcarcinomas, and follicular thyroid carcinomas.

In specific embodiments, the cancer is selected from germ cell tumors.In particular embodiments, the cancer is selected from the groupconsisting of malignant extracranial germ cell tumors and malignantextragonadal germ cell tumors. In specific instances of theseembodiments, the malignant extragonadal germ cell tumors are selectedfrom the group consisting of nonseminomas and seminomas.

In specific embodiments, the cancer is selected from heart tumors. Inparticular embodiments, the heart tumor is selected from the groupconsisting of malignant teratoma, lymphoma, rhabdomyosacroma,angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovialsarcoma.

In specific embodiments, the cell-proliferation disorder is selectedfrom benign papillomatosis, benign neoplastic diseases and gestationaltrophoblastic diseases. In particular embodiments, the benign neoplasticdisease is selected from skin papilloma (warts) and genital papilloma.In particular embodiments, the gestational trophoblastic disease isselected from the group consisting of hydatidiform moles, andgestational trophoblastic neoplasia (e.g., invasive moles,choriocarcinomas, placental-site trophoblastic tumors, and epithelioidtrophoblastic tumors).

In some embodiments, the subject has melanoma. The melanoma may be atearly stage or at late stage. In some embodiments, the subject hascolorectal cancer. The colorectal cancer may be at early stage or atlate stage. In some embodiments, the subject has non-small cell lungcancer. The non-small cell lung cancer may be at early stage or at latestage. In some embodiments, the subject has pancreatic cancer. Thepancreatic cancer may be at early stage or late state. In someembodiments, the subject has a hematological malignancy. Thehematological malignancy may be at early stage or late stage. In someembodiments, the subject has ovarian cancer. The ovarian cancer may beat early stage or at late stage. In some embodiments, the subject hasbreast cancer. The breast cancer may be at early stage or at late stage.In some embodiments, the subject has renal cell carcinoma. The renalcell carcinoma may be at early stage or at late stage. In someembodiments, the cancer has elevated levels of T-cell infiltration.

In some embodiments, cancers treatable with compounds of the presentdisclosure include melanoma (e.g., metastatic malignant melanoma), renalcancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormonerefractory prostate adenocarcinoma), breast cancer, triple-negativebreast cancer, colon cancer and lung cancer (e.g. non-small cell lungcancer and small cell lung cancer). Additionally, the disclosureincludes refractory or recurrent malignancies whose growth may beinhibited using the compounds of the disclosure.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasiasyndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiplemyeloma, cutaneous T-cell lymphoma, Waldenstrom's Macroglubulinemia,hairy cell lymphoma, chronic myelogenic lymphoma and Burkitt's lymphoma.

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, andteratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer, bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma).

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Exemplary nervous system cancers include cancers of the skull (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors), and spinal cord (neurofibroma, meningioma, glioma,sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

Exemplary gynecological cancers include cancers of the uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, molesdysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In someembodiments, diseases and indications that are treatable using thecompounds of the present disclosure include, but are not limited to,sickle cell disease (e.g., sickle cell anemia), triple-negative breastcancer (TNBC), myelodysplastic syndromes, testicular cancer, bile ductcancer, esophageal cancer, and urothelial carcinoma.

Exemplary head and neck cancers include glioblastoma, melanoma,rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas,adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer,nasal and paranasal cancers, thyroid and parathyroid cancers.

In some embodiments, HPK1 inhibitors may be used to treat tumorsproducing PGE2 (e.g. Cox-2 overexpressing tumors) and/or adenosine (CD73and CD39 over-expressing tumors). Overexpression ofCox-2 has beendetected in a number of tumors, such as colorectal, breast, pancreaticand lung cancers, where it correlates with a poor prognosis.Overexpression of COX-2 has been reported in hematological cancer modelssuch as RAJI (Burkitt's lymphoma) and U937 (acute promonocytic leukemia)as well as in patient's blast cells. CD73 is up-regulated in varioushuman carcinomas including those of colon, lung, pancreas and ovary.Importantly, higher expression levels of CD73 are associated with tumorneovascularization, invasiveness, and metastasis and with shorterpatient survival time in breast cancer.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

The presently disclosed compounds may be administered in any suitablemanner known in the art. In some embodiments, the compound of theinvention or a pharmaceutically acceptable salt, prodrug, metabolite, orderivative thereof is administered intravenously, intramuscularly,subcutaneously, topically, orally, transdermally, intraperitoneally,intraorbitally, by implantation, by inhalation, intrathecally,intraventricularly, intratumorally, or intranasally.

In some embodiments, the HPK1 antagonist is administered continuously.In other embodiments, the HPK1 antagonist is administeredintermittently. Moreover, treatment of a subject with an effectiveamount of a HPK1 antagonist can include a single treatment or caninclude a series of treatments.

It is understood that appropriate doses of the active compound dependsupon a number of factors within the knowledge of the ordinarily skilledphysician or veterinarian. The dose(s) of the active compound will vary,for example, depending upon the age, body weight, general health,gender, and diet of the subject, the time of administration, the routeof administration, the rate of excretion, and any drug combination.

It will also be appreciated that the effective dosage of a compound ofthe invention or a pharmaceutically acceptable salt, prodrug,metabolite, or derivative thereof used for treatment may increase ordecrease over the course of a particular treatment. Changes in dosagemay result and become apparent from the results of diagnostic assays.

In some embodiments, the HPK1 antagonist is administered to the subjectat a dose of between about 0.001 μg/kg and about 1000 mg/kg, includingbut not limited to about 0.001 μg/kg, 0.01 μg/kg, 0.05 μg/kg, 0.1 μg/kg,0.5 μg/kg, 1 μg/kg, 10 μg/kg, 25 μg/kg, 50 μg/kg, 100 μg/kg, 250 μg/kg,500 μg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 100 mg/kg,and 200 mg/kg.

In the methods described herein, the method can further compriseadministering a chemotherapeutic agent to the subject. In certainaspects of this embodiment, the chemotherapeutic agent is administeredto the subject simultaneously with the compound or the composition. Incertain aspects of this embodiment, the chemotherapeutic agent isadministered to the subject prior to administration of the compound orthe composition. In certain aspects of this embodiment, thechemotherapeutic agent is administered to the subject afteradministration of the compound or the composition.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

The term “administration” or “administering” includes routes ofintroducing the compound(s) to a subject to perform their intendedfunction. Examples of routes of administration which can be used includeinjection (subcutaneous, intravenous, parenterally, intraperitoneally,intrathecal), topical, oral, inhalation, rectal and transdermal.

The term “effective amount” includes an amount effective, at dosages andfor periods of time necessary, to achieve the desired result. Aneffective amount of compound may vary according to factors such as thedisease state, age, and weight of the subject, and the ability of thecompound to elicit a desired response in the subject. Dosage regimensmay be adjusted to provide the optimum therapeutic response.

The phrases “systemic administration,” “administered systemically”,“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound(s), drug or other material,such that it enters the patient's system and, thus, is subject tometabolism and other like processes.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein. In the case of cancer, the therapeuticallyeffective amount of the drug may reduce the number of cancer cells;reduce the tumor size; inhibit (i.e., slow to some extent and preferablystop) cancer cell infiltration into peripheral organs; inhibit (i.e.,slow to some extent and preferably stop) tumor metastasis; inhibit, tosome extent, tumor growth; and/or relieve to some extent one or more ofthe symptoms associated with the cancer. To the extent the drug mayprevent growth and/or kill existing cancer cells, it may be cytostaticand/or cytotoxic. For cancer therapy, efficacy can be measured, forexample, by assessing the time to disease progression (TTP) and/ordetermining the response rate (RR).

The term “subject” refers to animals such as mammals, including, but notlimited to, primates (e.g., humans), cows, sheep, goats, horses, dogs,cats, rabbits, rats, mice and the like. In certain embodiments, thesubject is a human.

Combination Therapies

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents, which are normally administered to treatthat condition, may be administered in combination with compounds andcompositions of this invention. As used herein, additional therapeuticagents that are normally administered to treat a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.”

In certain embodiments, a provided combination, or composition thereof,is administered in combination with another therapeutic agent.

Examples of agents the combinations of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept® and Excelon®; treatments for HIV such asritonavir; treatments for Parkinson's Disease such as L-DOPA/carbidopa,entacapone, ropinrole, pramipexole, bromocriptine, pergolide,trihexephendyl, and amantadine; agents for treating Multiple Sclerosis(MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, andmitoxantrone; treatments for asthma such as albuterol and Singulair®;agents for treating schizophrenia such as zyprexa, risperdal, seroquel,and haloperidol; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporin,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; agents thatprolong or improve pharmacokinetics such as cytochrome P450 inhibitors(i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g.,ketokenozole and ritonavir), and agents for treating immunodeficiencydisorders such as gamma globulin.

In certain embodiments, combination therapies of the present invention,or a pharmaceutically acceptable composition thereof, are administeredin combination with a monoclonal antibody or an siRNA therapeutic.

Those additional agents may be administered separately from a providedcombination therapy, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a combination ofthe present invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

In one embodiment, the present invention provides a compositioncomprising a compound of formula I and one or more additionaltherapeutic agents. The therapeutic agent may be administered togetherwith a compound of formula I, or may be administered prior to orfollowing administration of a compound of formula I. Suitabletherapeutic agents are described in further detail below. In certainembodiments, a compound of formula I may be administered up to 5minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours,12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hoursbefore the therapeutic agent. In other embodiments, a compound offormula I may be administered up to 5 minutes, 10 minutes, 15 minutes,30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14hours, 15 hours, 16 hours, 17 hours, or 18 hours following thetherapeutic agent.

In another embodiment, the present invention provides a method oftreating an inflammatory disease, disorder or condition by administeringto a patient in need thereof a compound of formula I and one or moreadditional therapeutic agents. Such additional therapeutic agents may besmall molecules or recombinant biologic agents and include, for example,acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, probenecid,allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®),antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine(Aralen®), methotrexate (Rheumatrex®), gold salts such as goldthioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin(Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine(Imuran®), cyclophosphami de (Cytoxan®), chlorambucil (Leukeran®),cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agentssuch as etanercept (Enbrel®), infliximab (Remicade®), golimumab(Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®),“anti-IL-1” agents such as anakinra (Kineret®) and rilonacept(Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such astofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®), “anti-IL-6” agents such astocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc®or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulantssuch as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®),antidiarrheals such as diphenoxylate (Lomotil®) and loperamide(Imodium®), bile acid binding agents such as cholestyramine, alosetron(Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk ofMagnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® andSenokot®, anticholinergics or antispasmodics such as dicyclomine(Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA,Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®),pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®),salmeterol xinafoate (Serevent®) and formoterol (Foradil®),anticholinergic agents such as ipratropium bromide (Atrovent®) andtiotropium (Spiriva®), inhaled corticosteroids such as beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), andflunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium(Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®,Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such asomalizumab (Xolair®), nucleoside reverse transcriptase inhibitors suchas zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine(Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine(Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®),lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine(Hivid®), non-nucleoside reverse transcriptase inhibitors such asdelavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®)and etravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), doxorubicin(Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), anddexamethasone (Decadron®) in combination with lenalidomide (Revlimid®),or any combination(s) thereof.

In another embodiment, the present invention provides a method oftreating rheumatoid arthritis comprising administering to a patient inneed thereof a compound of formula I and one or more additionaltherapeutic agents selected from non-steroidal anti-inflammatory drugs(NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) andcelecoxib, corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, sulfasalazine(Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) andchloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such asgold thioglucose (Solganal®), gold thiomalate (Myochrysine®) andauranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®),azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil(Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and“anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®),golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab(Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept(Arcalyst®), antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®) and “anti-IL-6” agents such astocilizumab (Actemra®).

In some embodiments, the present invention provides a method of treatingosteoarthritis comprising administering to a patient in need thereof acompound of formula I and one or more additional therapeutic agentsselected from acetaminophen, non-steroidal anti-inflammatory drugs(NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) andcelecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®)and monoclonal antibodies such as tanezumab.

In some embodiments, the present invention provides a method of treatingcutaneous lupus erythematosus or systemic lupus erythematosus comprisingadministering to a patient in need thereof a compound of formula I andone or more additional therapeutic agents selected from acetaminophen,non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin,ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroidssuch as prednisone, prednisolone, methylprednisolone, hydrocortisone,and the like, antimalarials such as hydroxychloroquine (Plaquenil®) andchloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate(Rheumatrex®), azathioprine (Imuran®) and anticoagulants such as heparin(Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

In some embodiments, the present invention provides a method of treatingCrohn's disesase, ulcerative colitis, or inflammatory bowel diseasecomprising administering to a patient in need thereof a compound offormula I and one or more additional therapeutic agents selected frommesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrheals such asdiphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid bindingagents such as cholestyramine, alosetron (Lotronex®), lubiprostone(Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol(MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics orantispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies,steroids, and antibiotics such as Flagyl or ciprofloxacin.

In some embodiments, the present invention provides a method of treatingasthma comprising administering to a patient in need thereof a compoundof formula I and one or more additional therapeutic agents selected fromSingulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil®HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterolacetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterolxinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agentssuch as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®),inhaled corticosteroids such as prednisone, prednisolone, beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®),flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolynsodium (Intal®), methylxanthines such as theophylline (Theo-Dur®,Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgEantibodies such as omalizumab (Xolair®).

In some embodiments, the present invention provides a method of treatingCOPD comprising administering to a patient in need thereof a compound offormula I and one or more additional therapeutic agents selected frombeta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA),levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate(Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate(Serevent®) and formoterol (Foradil®), anticholinergic agents such asipratropium bromide (Atrovent®) and tiotropium (Spiriva®),methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®,Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such asprednisone, prednisolone, beclomethasone dipropionate (Beclovent®,Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone(Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®,Symbicort®, and Dulera®,

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a compound of formula I and one or moreadditional therapeutic agents selected from rituximab (Rituxan®),cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®),vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, aBTK inhibitor, a JAK/pan-JAK inhibitor, a PI3K inhibitor, a SYKinhibitor, and combinations thereof.

In another embodiment, the present invention provides a method oftreating a solid tumor comprising administering to a patient in needthereof a compound of formula I and one or more additional therapeuticagents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®),doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, ahedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor,a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a compound of formula I and a Hedgehog (Hh)signaling pathway inhibitor. In some embodiments, the hematologicalmalignancy is DLBCL (Ramirez et al “Defining causative factorscontributing in the activation of hedgehog signaling in diffuse largeB-cell lymphoma” Leuk. Res. (2012), published online July 17, andincorporated herein by reference in its entirety).

In another embodiment, the present invention provides a method oftreating diffuse large B-cell lymphoma (DLBCL) comprising administeringto a patient in need thereof a compound of formula I and one or moreadditional therapeutic agents selected from rituximab (Rituxan®),cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®),vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, andcombinations thereof.

In another embodiment, the present invention provides a method oftreating multiple myeloma comprising administering to a patient in needthereof a compound of formula I and one or more additional therapeuticagents selected from bortezomib (Velcade®), and dexamethasone(Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, aJAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYKinhibitor in combination with lenalidomide (Revlimid®).

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I and a BTKinhibitor, wherein the disease is selected from inflammatory boweldisease, arthritis, cutaneous lupus erythematosus, systemic lupuserythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura(ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis,Still's disease, juvenile arthritis, diabetes, myasthenia gravis,Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmunethyroiditis, Sjogren's syndrome, multiple sclerosis, systemic sclerosis,Lyme neuroborreliosis, Guillain-Barre syndrome, acute disseminatedencephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome,ankylosing spondylosis, antiphospholipid antibody syndrome, aplasticanemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia,celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenicpurpura, optic neuritis, scleroderma, primary biliary cirrhosis,Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warmautoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis,alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia,membranous glomerulonephropathy, endometriosis, interstitial cystitis,pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma,vulvodynia, a hyperproliferative disease, rejection of transplantedorgans or tissues, Acquired Immunodeficiency Syndrome (AIDS, also knownas HIV), type 1 diabetes, graft versus host disease, transplantation,transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens,latex, drugs, foods, insect poisons, animal hair, animal dander, dustmites, or cockroach calyx), type I hypersensitivity, allergicconjunctivitis, allergic rhinitis, and atopic dermatitis, asthma,appendicitis, atopic dermatitis, asthma, allergy, blepharitis,bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn'sdisease, cystitis, dacryoadenitis, dermatitis, dermatomyositis,encephalitis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitissuppurativa, immunoglobulin A nephropathy, interstitial lung disease,laryngitis, mastitis, meningitis, myelitis myocarditis, myositis,nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis,parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,pneumonitis, pneumonia, polymyositis, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis,vasculitis, or vulvitis, B-cell proliferative disorder, e.g., diffuselarge B cell lymphoma, follicular lymphoma, chronic lymphocyticlymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia,B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrommacroglobulinemia, splenic marginal zone lymphoma, multiple myeloma(also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin'slymphoma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodalmarginal zone B cell lymphoma, mantle cell lymphoma, mediastinal(thymic) large B cell lymphoma, intravascular large B cell lymphoma,primary effusion lymphoma, Burkitt lymphoma/leukemia, or lymphomatoidgranulomatosis, breast cancer, prostate cancer, or cancer of the mastcells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma,systemic mastocytosis), bone cancer, colorectal cancer, pancreaticcancer, diseases of the bone and joints including, without limitation,rheumatoid arthritis, seronegative spondyloarthropathies (includingankylosing spondylitis, psoriatic arthritis and Reiter's disease),Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis,bone cancer, bone metastasis, a thromboembolic disorder, (e.g.,myocardial infarct, angina pectoris, reocclusion after angioplasty,restenosis after angioplasty, reocclusion after aortocoronary bypass,restenosis after aortocoronary bypass, stroke, transitory ischemia, aperipheral arterial occlusive disorder, pulmonary embolism, deep venousthrombosis), inflammatory pelvic disease, urethritis, skin sunburn,sinusitis, pneumonitis, encephalitis, meningitis, myocarditis,nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis,dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus,agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowelsyndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection,hyperacute rejection of transplanted organs, asthma, allergic rhinitis,chronic obstructive pulmonary disease (COPD), autoimmune polyglandulardisease (also known as autoimmune polyglandular syndrome), autoimmunealopecia, pernicious anemia, glomerulonephritis, dermatomyositis,multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic andthrombocytopenic states, Goodpasture's syndrome, atherosclerosis,Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes,septic shock, cutaneous lupus erythematosus, systemic lupuserythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenilearthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura,Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto'sthyroiditis, atopic dermatitis, degenerative joint disease, vitiligo,autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet's disease,scleraderma, mycosis fungoides, acute inflammatory responses (such asacute respiratory distress syndrome and ischemia/reperfusion injury),and Graves' disease.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I and a PI3Kinhibitor, wherein the disease is selected from a cancer, aneurodegenative disorder, an angiogenic disorder, a viral disease, anautoimmune disease, an inflammatory disorder, a hormone-related disease,conditions associated with organ transplantation, immunodeficiencydisorders, a destructive bone disorder, a proliferative disorder, aninfectious disease, a condition associated with cell death,thrombin-induced platelet aggregation, chronic myelogenous leukemia(CML), chronic lymphocytic leukemia (CLL), liver disease, pathologicimmune conditions involving T cell activation, a cardiovasculardisorder, and a CNS disorder.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I and a PI3Kinhibitor, wherein the disease is selected from benign or malignanttumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cellcarcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach,gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung,vagina, endometrium, cervix, testis, genitourinary tract, esophagus,larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas,multiple myeloma or gastrointestinal cancer, especially colon carcinomaor colorectal adenoma or a tumor of the neck and head, an epidermalhyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, aneoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, (including, for example,non-Hodgkin's Lymphoma (NHL) and Hodgkin's lymphoma (also termedHodgkin's or Hodgkin's disease)), a mammary carcinoma, follicularcarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma,melanoma, or a leukemia, diseases include Cowden syndrome,Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases inwhich the PI3K/PKB pathway is aberrantly activated, asthma of whatevertype or genesis including both intrinsic (non-allergic) asthma andextrinsic (allergic) asthma, mild asthma, moderate asthma, severeasthma, bronchitic asthma, exercise-induced asthma, occupational asthmaand asthma induced following bacterial infection, acute lung injury(ALI), adult/acute respiratory distress syndrome (ARDS), chronicobstructive pulmonary, airways or lung disease (COPD, COAD or COLD),including chronic bronchitis or dyspnea associated therewith, emphysema,as well as exacerbation of airways hyperreactivity consequent to otherdrug therapy, in particular other inhaled drug therapy, bronchitis ofwhatever type or genesis including, but not limited to, acute,arachidic, catarrhal, croupus, chronic or phthinoid bronchitis,pneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis,Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particularmetazoan) infestation (including tropical eosinophilia),bronchopulmonary aspergillosis, polyarteritis nodosa (includingChurg-Strauss syndrome), eosinophilic granuloma and eosinophil-relateddisorders affecting the airways occasioned by drug-reaction, psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, pemphisus, epidermolysis bullosa acquisita,conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis,diseases affecting the nose including allergic rhinitis, andinflammatory disease in which autoimmune reactions are implicated orhaving an autoimmune component or etiology, including autoimmunehematological disorders (e.g. hemolytic anemia, aplastic anemia, purered cell anemia and idiopathic thrombocytopenia), cutaneous lupuserythematosus, systemic lupus erythematosus, rheumatoid arthritis,polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis,chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome,idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerativecolitis and Crohn's disease), endocrine opthalmopathy, Grave's disease,sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiplesclerosis, primary biliary cirrhosis, uveitis (anterior and posterior),keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitiallung fibrosis, psoriatic arthritis and glomerulonephritis (with andwithout nephrotic syndrome, e.g. including idiopathic nephrotic syndromeor minal change nephropathy, restenosis, cardiomegaly, atherosclerosis,myocardial infarction, ischemic stroke and congestive heart failure,Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, and cerebral ischemia, and neurodegenerativedisease caused by traumatic injury, glutamate neurotoxicity and hypoxia.

In some embodiments the present invention provides a method of treatingor lessening the severity of a disease comprising administering to apatient in need thereof a compound of formula I and a Bcl-2 inhibitor,wherein the disease is an inflammatory disorder, an autoimmune disorder,a proliferative disorder, an endocrine disorder, a neurologicaldisorder, or a disorder associated with transplantation. In someembodiments, the disorder is a proliferative disorder, lupus, or lupusnephritis. In some embodiments, the proliferative disorder is chroniclymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease,small-cell lung cancer, non-small-cell lung cancer, myelodysplasticsyndrome, lymphoma, a hematological neoplasm, or solid tumor.

In some embodiments, the disease is an autoimmune disorder, aninflammatory disorder, a proliferative disorder, an endocrine disorder,a neurological disorder, or a disorder associated with transplantation.In some embodiments the JH2 binding compound is a compound of formula I.Other suitable JH2 domain binding compounds include those described inWO2014074660A1, WO2014074661A1, WO2015089143A1, the entirety of each ofwhich is incorporated herein by reference. Suitable JH1 domain bindingcompounds include those described in WO2015131080A1, the entirety ofwhich is incorporated herein by reference.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of anautoimmune disorder, an inflammatory disorder, a proliferative disorder,an endocrine disorder, a neurological disorder, or a disorder associatedwith transplantation. The exact amount required will vary from subjectto subject, depending on the species, age, and general condition of thesubject, the severity of the infection, the particular agent, its modeof administration, and the like. Compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofinhibiting protein kinase activity in a biological sample comprising thestep of contacting said biological sample with a compound of thisinvention, or a composition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting HPK1, or a mutant thereof, activity in a biological samplecomprising the step of contacting said biological sample with a compoundof this invention, or a composition comprising said compound. In certainembodiments, the invention relates to a method of irreversiblyinhibiting HPK1, or a mutant thereof, activity in a biological samplecomprising the step of contacting said biological sample with a compoundof this invention, or a composition comprising said compound.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof biopsied material obtainedfrom a mammal or extracts thereof; and blood, saliva, urine, feces,semen, tears, or other body fluids or extracts thereof.

Inhibition of HPK1 (or a mutant thereof) activity in a biological sampleis useful for a variety of purposes that are known to one of skill inthe art. Examples of such purposes include, but are not limited to,blood transfusion, organ-transplantation, biological specimen storage,and biological assays.

Another embodiment of the present invention relates to a method ofinhibiting protein kinase activity in a patient comprising the step ofadministering to said patient a compound of the present invention, or acomposition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting activity of HPK1, or a mutant thereof, in a patientcomprising the step of administering to said patient a compound of thepresent invention, or a composition comprising said compound. Accordingto certain embodiments, the invention relates to a method of reversiblyor irreversibly inhibiting one or more of HPK1, or a mutant thereof,activity in a patient comprising the step of administering to saidpatient a compound of the present invention, or a composition comprisingsaid compound. In other embodiments, the present invention provides amethod for treating a disorder mediated by HPK1, or a mutant thereof, ina patient in need thereof, comprising the step of administering to saidpatient a compound according to the present invention orpharmaceutically acceptable composition thereof. Such disorders aredescribed in detail herein.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition, may also be present in the compositions of thisinvention. As used herein, additional therapeutic agents that arenormally administered to treat a particular disease, or condition, areknown as “appropriate for the disease, or condition, being treated.”

A compound of the current invention may also be used to advantage incombination with other therapeutic compounds. In some embodiments, theother therapeutic compounds are antiproliferative compounds. Suchantiproliferative compounds include, but are not limited to aromataseinhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase IIinhibitors; microtubule active compounds; alkylating compounds; histonedeacetylase inhibitors; compounds which induce cell differentiationprocesses; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors;antineoplastic antimetabolites; platin compounds; compoundstargeting/decreasing a protein or lipid kinase activity and furtheranti-angiogenic compounds; compounds which target, decrease or inhibitthe activity of a protein or lipid phosphatase; gonadorelin agonists;anti-androgens; methionine aminopeptidase inhibitors; matrixmetalloproteinase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507),17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin,NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from ConformaTherapeutics; temozolomide (Temodal®); kinesin spindle proteininhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, orpentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such asARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 fromPfizer and leucovorin. The term “aromatase inhibitor” as used hereinrelates to a compound which inhibits estrogen production, for instance,the conversion of the substrates androstenedione and testosterone toestrone and estradiol, respectively. The term includes, but is notlimited to steroids, especially atamestane, exemestane and formestaneand, in particular, non-steroids, especially aminoglutethimide,roglethimide, pyridoglutethimide, trilostane, testolactone,ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestaneis marketed under the trade name Aromasin™. Formestane is marketed underthe trade name Lentaron™. Fadrozole is marketed under the trade nameAfema™. Anastrozole is marketed under the trade name Arimidex™ Letrozoleis marketed under the trade names Femara™ or Femar™. Aminoglutethimideis marketed under the trade name Orimeten™. A combination of theinvention comprising a chemotherapeutic agent which is an aromataseinhibitor is particularly useful for the treatment of hormone receptorpositive tumors, such as breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen is marketed under the trade nameNolvadex™. Raloxifene hydrochloride is marketed under the trade nameEvista™. Fulvestrant can be administered under the trade name Faslodex™.A combination of the invention comprising a chemotherapeutic agent whichis an anti estrogen is particularly useful for the treatment of estrogenreceptor positive tumors, such as breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (Casodex™). The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin and goserelin acetate. Goserelin can be administeredunder the trade name Zoladex™.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148. Irinotecan can be administered, e.g. in the formas it is marketed, e.g. under the trademark Camptosar™. Topotecan ismarketed under the trade name Hycamptin™.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, such as Caelyx™) daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide is marketed under the trade name Etopophos™. Teniposide ismarketed under the trade name VM 26-Bristol Doxorubicin is marketedunder the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketedunder the trade name Farmorubicin™. Idarubicin is marketed. under thetrade name Zavedos™. Mitoxantrone is marketed under the trade nameNovantron.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing compounds and microtublin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;cochicine and epothilones and derivatives thereof. Paclitaxel ismarketed under the trade name Taxol™. Docetaxel is marketed under thetrade name Taxotere™. Vinblastine sulfate is marketed under the tradename Vinblastin R.P™. Vincristine sulfate is marketed under the tradename Farmistin™.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide is marketed under the trade name Cyclostin™.Ifosfamide is marketed under the trade name Holoxan™.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes, but is not limited to,suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabineis marketed under the trade name Xeloda™. Gemcitabine is marketed underthe trade name Gemzar™.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark Carboplat™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark Eloxatin™.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, such as a) compounds targeting,decreasing or inhibiting the activity of the platelet-derived growthfactor-receptors (PDGFR), such as compounds which target, decrease orinhibit the activity of PDGFR, especially compounds which inhibit thePDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, suchas imatinib, SU101, SU6668 and GFB-111; b) compounds targeting,decreasing or inhibiting the activity of the fibroblast growthfactor-receptors (FGFR); c) compounds targeting, decreasing orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as compounds which target, decrease or inhibit theactivity of IGF-IR, especially compounds which inhibit the kinaseactivity of IGF-I receptor, or antibodies that target the extracellulardomain of IGF-I receptor or its growth factors; d) compounds targeting,decreasing or inhibiting the activity of the Trk receptor tyrosinekinase family, or ephrin B4 inhibitors; e) compounds targeting,decreasing or inhibiting the activity of the AxI receptor tyrosinekinase family; f) compounds targeting, decreasing or inhibiting theactivity of the Ret receptor tyrosine kinase; g) compounds targeting,decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosinekinase, such as imatinib; h) compounds targeting, decreasing orinhibiting the activity of the C-kit receptor tyrosine kinases, whichare part of the PDGFR family, such as compounds which target, decreaseor inhibit the activity of the c-Kit receptor tyrosine kinase family,especially compounds which inhibit the c-Kit receptor, such as imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, such asan N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825); j) compounds targeting, decreasing or inhibitingthe activity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK,PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, BTK and TEC family, and/or membersof the cyclin-dependent kinase family (CDK) including staurosporinederivatives, such as midostaurin; examples of further compounds includeUCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; llmofosine; RO318220 and RO 320432; GO 6976; lsis 3521; LY333531/LY379196;isochinoline compounds; FTIs; PD184352 or QAN697 (a P13K inhibitor) orAT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibitingthe activity of protein-tyrosine kinase inhibitors, such as compoundswhich target, decrease or inhibit the activity of protein-tyrosinekinase inhibitors include imatinib mesylate (Gleevec™) or tyrphostinsuch as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer;Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); 1) compounds targeting, decreasing orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFR₁ ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as compounds which target,decrease or inhibit the activity of the epidermal growth factor receptorfamily are especially compounds, proteins or antibodies which inhibitmembers of the EGF receptor tyrosine kinase family, such as EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab(Erbitux™), Iressa, Tarceva, OSI-774, C1-1033, EKB-569, GW-2016, E1.1,E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting,decreasing or inhibiting the activity of the c-Met receptor, such ascompounds which target, decrease or inhibit the activity of c-Met,especially compounds which inhibit the kinase activity of c-Metreceptor, or antibodies that target the extracellular domain of c-Met orbind to HGF, n) compounds targeting, decreasing or inhibiting the kinaseactivity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/orpan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib,pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, andruxolitinib; o) compounds targeting, decreasing or inhibiting the kinaseactivity of PI3 kinase (PI3K) including but not limited to ATU-027,SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib,pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, andidelalisib; and; and q) compounds targeting, decreasing or inhibitingthe signaling effects of hedgehog protein (Hh) or smoothened receptor(SMO) pathways, including but not limited to cyclopamine, vismodegib,itraconazole, erismodegib, and IPI-926 (saridegib).

The term “PI3K inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against one or more enzymes in thephosphatidylinositol-3-kinase family, including, but not limited toPI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α,p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87.Examples of PI3K inhibitors useful in this invention include but are notlimited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474,buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147,XL-765, and idelalisib.

The term “BTK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against Bruton's Tyrosine Kinase(BTK), including, but not limited to AVL-292 and ibrutinib.

The term “SYK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against spleen tyrosine kinase(SYK), including but not limited to PRT-062070, R-343, R-333, Excellair,PRT-062607, and fostamatinib.

The term “Bcl-2 inhibitor” as used herein includes, but is not limitedto compounds having inhibitory activity against B-cell lymphoma 2protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737,apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogsthereof), dual Bcl-2/Bcl-xL inhibitors (InfinityPharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1(and analogs thereof; see WO2008118802), navitoclax (and analogsthereof, see U.S. Pat. No. 7,390,799), NH-1 (Shenayng PharmaceuticalUniversity), obatoclax (and analogs thereof, see WO2004106328), S-001(Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), andvenetoclax. In some embodiments the Bcl-2 inhibitor is a small moleculetherapeutic. In some embodiments the Bcl-2 inhibitor is apeptidomimetic.

Further examples of BTK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2008039218 and WO2011090760, the entirety of which areincorporated herein by reference.

Further examples of SYK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2003063794, WO2005007623, and WO2006078846, the entirety ofwhich are incorporated herein by reference.

Further examples of PI3K inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2004019973, WO2004089925, WO2007016176, U.S. Pat. No.8,138,347, WO2002088112, WO2007084786, WO2007129161, WO2006122806,WO2005113554, and WO2007044729 the entirety of which are incorporatedherein by reference.

Further examples of JAK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2009114512, WO2008109943, WO2007053452, WO2000142246, andWO2007070514, the entirety of which are incorporated herein byreference.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (Thalomid™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination withcompounds of the invention include, but are not limited to bortezomib,disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A,carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes include, but arenot limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- orδ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, such as5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. Etridonic acid is marketedunder the trade name Didronel™. Clodronic acid is marketed under thetrade name Bonefos™. Tiludronic acid is marketed under the trade nameSkelid™. Pamidronic acid is marketed under the trade name Aredia™.Alendronic acid is marketed under the trade name Fosamax™. Ibandronicacid is marketed under the trade name Bondranat™. Risedronic acid ismarketed under the trade name Actonel™. Zoledronic acid is marketedunder the trade name Zometa™. The term “mTOR inhibitors” relates tocompounds which inhibit the mammalian target of rapamycin (mTOR) andwhich possess antiproliferative activity such as sirolimus (Rapamune®),everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88. The term “biological responsemodifier” as used herein refers to a lymphokine or interferons.

The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras; for example, a “farnesyltransferase inhibitor” such as L-744832, DK8G557 or R115777(Zarnestra™). The term “telomerase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of telomerase.Compounds which target, decrease or inhibit the activity of telomeraseare especially compounds which inhibit the telomerase receptor, such astelomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase include, but are not limited to, bengamideor a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasomeinclude, but are not limited to, Bortezomib (Velcade™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, which are compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase, and Bcl-2 inhibitors.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,such as PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and2C4 Antibody. By antibodies is meant intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of thecurrent invention can be used in combination with standard leukemiatherapies, especially in combination with therapies used for thetreatment of AML. In particular, compounds of the current invention canbe administered in combination with, for example, farnesyl transferaseinhibitors and/or other drugs useful for the treatment of AML, such asDaunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone,Idarubicin, Carboplatinum and PKC412. In some embodiments, the presentinvention provides a method of treating AML associated with an ITDand/or D835Y mutation, comprising administering a compound of thepresent invention together with a one or more FLT3 inhibitors. In someembodiments, the FLT3 inhibitors are selected from quizartinib (AC220),a staurosporine derivative (e.g. midostaurin or lestaurtinib),sorafenib, tandutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302,NMS-P948, AST-487, G-749, SB-1317, S-209, SC-110219, AKN-028,fedratinib, tozasertib, and sunitinib. In some embodiments, the FLT3inhibitors are selected from quizartinib, midostaurin, lestaurtinib,sorafenib, and sunitinib.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidineanalog, which is the 2′-alpha-hydroxy ribose (arabinoside) derivative ofdeoxycytidine. Also included is the purine analog of hypoxanthine,6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds whichtarget, decrease or inhibit activity of histone deacetylase (HDAC)inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid(SAHA) inhibit the activity of the enzymes known as histonedeacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228(formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat.No. 6,552,065 including, but not limited to,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt. Somatostatin receptor antagonists as used herein refer tocompounds which target, treat or inhibit the somatostatin receptor suchas octreotide, and SOM230. Tumor cell damaging approaches refer toapproaches such as ionizing radiation. The term “ionizing radiation”referred to above and hereinafter means ionizing radiation that occursas either electromagnetic rays (such as X-rays and gamma rays) orparticles (such as alpha and beta particles). Ionizing radiation isprovided in, but not limited to, radiation therapy and is known in theart. See Hellman, Principles of Radiation Therapy, Cancer, in Principlesand Practice of Oncology, Devita et al., Eds., 4^(th) Edition, Vol. 1,pp. 248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors.The term “EDG binders” as used herein refers to a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720. The term “ribonucleotide reductase inhibitors” refers topyrimidine or purine nucleoside analogs including, but not limited to,fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,5-fluorouracil, cladribine, 6-mercaptopurine (especially in combinationwith ara-C against ALL) and/or pentostatin. Ribonucleotide reductaseinhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF such as1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate;Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474;SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGFreceptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such asMacugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™)

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as Visudyne™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such asfluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plantalkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The compounds of the invention are also useful as co-therapeuticcompounds for use in combination with other drug substances such asanti-inflammatory, bronchodilatory or antihistamine drug substances,particularly in the treatment of obstructive or inflammatory airwaysdiseases such as those mentioned hereinbefore, for example aspotentiators of therapeutic activity of such drugs or as a means ofreducing required dosaging or potential side effects of such drugs. Acompound of the invention may be mixed with the other drug substance ina fixed pharmaceutical composition or it may be administered separately,before, simultaneously with or after the other drug substance.Accordingly the invention includes a combination of a compound of theinvention as hereinbefore described with an anti-inflammatory,bronchodilatory, antihistamine or anti-tussive drug substance, saidcompound of the invention and said drug substance being in the same ordifferent pharmaceutical composition.

Suitable anti-inflammatory drugs include steroids, in particularglucocorticosteroids such as budesonide, beclamethasone dipropionate,fluticasone propionate, ciclesonide or mometasone furoate; non-steroidalglucocorticoid receptor agonists; LTB4 antagonists such LY293111,CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4antagonists such as montelukast and zafirlukast; PDE4 inhibitors suchcilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A(Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline(Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281(Asta Medica), CDC-801 (Celgene), SeICID™ CC-10004 (Celgene),VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2aagonists; A2b antagonists; and beta-2 adrenoceptor agonists such asalbuterol (salbutamol), metaproterenol, terbutaline, salmeterolfenoterol, procaterol, and especially, formoterol and pharmaceuticallyacceptable salts thereof. Suitable bronchodilatory drugs includeanticholinergic or antimuscarinic compounds, in particular ipratropiumbromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), andglycopyrrolate.

Suitable antihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride,activastine, astemizole, azelastine, ebastine, epinastine, mizolastineand tefenadine.

Other useful combinations of compounds of the invention withanti-inflammatory drugs are those with antagonists of chemokinereceptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8,CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 andSCH-D, and Takeda antagonists such asN-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminiumchloride (TAK-770).

The structure of the active compounds identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

Exemplary Immuno-Oncology Agents

In some embodiments, one or more other therapeutic agent is animmuno-oncology agent. As used herein, the term “an immuno-oncologyagent” refers to an agent which is effective to enhance, stimulate,and/or up-regulate immune responses in a subject. In some embodiments,the administration of an immuno-oncology agent with a compound of theinvention has a synergic effect in treating a cancer.

An immuno-oncology agent can be, for example, a small molecule drug, anantibody, or a biologic or small molecule. Examples of biologicimmuno-oncology agents include, but are not limited to, cancer vaccines,antibodies, and cytokines. In some embodiments, an antibody is amonoclonal antibody. In some embodiments, a monoclonal antibody ishumanized or human.

In some embodiments, an immuno-oncology agent is (i) an agonist of astimulatory (including a co-stimulatory) receptor or (ii) an antagonistof an inhibitory (including a co-inhibitory) signal on T cells, both ofwhich result in amplifying antigen-specific T cell responses.

Certain of the stimulatory and inhibitory molecules are members of theimmunoglobulin super family (IgSF). One important family ofmembrane-bound ligands that bind to co-stimulatory or co-inhibitoryreceptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1),B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.Another family of membrane bound ligands that bind to co-stimulatory orco-inhibitory receptors is the TNF family of molecules that bind tocognate TNF receptor family members, which includes CD40 and CD40L,OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB),TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK,RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTOR,LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1,Lymphotoxin α/TNFβ, TNFR2, TNFα, LTβR, Lymphotoxin α1β2, FAS, FASL,RELT, DR6, TROY, NGFR.

In some embodiments, an immuno-oncology agent is a cytokine thatinhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and otherimmunosuppressive cytokines) or a cytokine that stimulates T cellactivation, for stimulating an immune response.

In some embodiments, a combination of a compound of the invention and animmuno-oncology agent can stimulate T cell responses. In someembodiments, an immuno-oncology agent is: (i) an antagonist of a proteinthat inhibits T cell activation (e.g., immune checkpoint inhibitors)such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1,BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP,PD1H, LAIRL TIM-1, and TIM-4; or (ii) an agonist of a protein thatstimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137),4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3and CD28H.

In some embodiments, an immuno-oncology agent is an antagonist ofinhibitory receptors on NK cells or an agonists of activating receptorson NK cells. In some embodiments, an immuno-oncology agent is anantagonist of KIR, such as lirilumab.

In some embodiments, an immuno-oncology agent is an agent that inhibitsor depletes macrophages or monocytes, including but not limited toCSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155(WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716,WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).

In some embodiments, an immuno-oncology agent is selected from agonisticagents that ligate positive costimulatory receptors, blocking agentsthat attenuate signaling through inhibitory receptors, antagonists, andone or more agents that increase systemically the frequency ofanti-tumor T cells, agents that overcome distinct immune suppressivepathways within the tumor microenvironment (e.g., block inhibitoryreceptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibitTregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab)or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes suchas IDO, or reverse/prevent T cell energy or exhaustion) and agents thattrigger innate immune activation and/or inflammation at tumor sites.

In some embodiments, an immuno-oncology agent is a CTLA-4 antagonist. Insome embodiments, a CTLA-4 antagonist is an antagonistic CTLA-4antibody. In some embodiments, an antagonistic CTLA-4 antibody is YERVOY(ipilimumab) or tremelimumab.

In some embodiments, an immuno-oncology agent is a PD-1 antagonist. Insome embodiments, a PD-1 antagonist is administered by infusion. In someembodiments, an immuno-oncology agent is an antibody or anantigen-binding portion thereof that binds specifically to a ProgrammedDeath-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments,a PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments,an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA(pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). In someembodiments, an immuno-oncology agent may be pidilizumab (CT-011). Insome embodiments, an immuno-oncology agent is a recombinant proteincomposed of the extracellular domain of PD-L2 (B7-DC) fused to the Fcportion of IgG1, called AMP-224.

In some embodiments, an immuno-oncology agent is a PD-L1 antagonist. Insome embodiments, a PD-L1 antagonist is an antagonistic PD-L1 antibody.In some embodiments, a PD-L1 antibody is MPDL3280A (RG7446;WO2010/077634), durvalumab (MEDI4736), BMS-936559 (WO2007/005874), andMSB0010718C (WO2013/79174).

In some embodiments, an immuno-oncology agent is a LAG-3 antagonist. Insome embodiments, a LAG-3 antagonist is an antagonistic LAG-3 antibody.In some embodiments, a LAG3 antibody is BMS-986016 (WO10/19570,WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO009/44273).

In some embodiments, an immuno-oncology agent is a CD137 (4-1BB)agonist. In some embodiments, a CD137 (4-1BB) agonist is an agonisticCD137 antibody. In some embodiments, a CD137 antibody is urelumab orPF-05082566 (WO12/32433).

In some embodiments, an immuno-oncology agent is a GITR agonist. In someembodiments, a GITR agonist is an agonistic GITR antibody. In someembodiments, a GITR antibody is BMS-986153, BMS-986156, TRX-518(WO006/105021, WO009/009116), or MK-4166 (WO11/028683).

In some embodiments, an immuno-oncology agent is an indoleamine(2,3)-dioxygenase (IDO) antagonist. In some embodiments, an IDOantagonist is selected from epacadostat (INCB024360, Incyte); indoximod(NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis);GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287(Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme thatbreaks down kynurenine (Kynase, Ikena Oncology, formerly known as KynTherapeutics); and NLG-919 (WO09/73620, WO009/1156652, WO11/56652,WO12/142237).

In some embodiments, an immuno-oncology agent is an OX40 agonist. Insome embodiments, an OX40 agonist is an agonistic OX40 antibody. In someembodiments, an OX40 antibody is MEDI-6383 or MEDI-6469.

In some embodiments, an immuno-oncology agent is an OX40L antagonist. Insome embodiments, an OX40L antagonist is an antagonistic OX40 antibody.In some embodiments, an OX40L antagonist is RG-7888 (WO06/029879).

In some embodiments, an immuno-oncology agent is a CD40 agonist. In someembodiments, a CD40 agonist is an agonistic CD40 antibody. In someembodiments, an immuno-oncology agent is a CD40 antagonist. In someembodiments, a CD40 antagonist is an antagonistic CD40 antibody. In someembodiments, a CD40 antibody is lucatumumab or dacetuzumab.

In some embodiments, an immuno-oncology agent is a CD27 agonist. In someembodiments, a CD27 agonist is an agonistic CD27 antibody. In someembodiments, a CD27 antibody is varlilumab.

In some embodiments, an immuno-oncology agent is MGA271 (to B7H3)(WO11/109400).

In some embodiments, an immuno-oncology agent is abagovomab,adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab,atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab,epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab,ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab,obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab,pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

In some embodiments, an immuno-oncology agent is an immunostimulatoryagent. For example, antibodies blocking the PD-1 and PD-L1 inhibitoryaxis can unleash activated tumor-reactive T cells and have been shown inclinical trials to induce durable anti-tumor responses in increasingnumbers of tumor histologies, including some tumor types thatconventionally have not been considered immunotherapy sensitive. See,e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al.(2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (OPDIVO®,Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558),has shown potential to improve the overall survival in patients with RCCwho had experienced disease progression during or after prioranti-angiogenic therapy.

In some embodiments, the immunomodulatory therapeutic specificallyinduces apoptosis of tumor cells. Approved immunomodulatory therapeuticswhich may be used in the present invention include pomalidomide(POMALYST®, Celgene); lenalidomide (REVLIMID®, Celgene); ingenolmebutate (PICATO®, LEO Pharma).

In some embodiments, an immuno-oncology agent is a cancer vaccine. Insome embodiments, the cancer vaccine is selected from sipuleucel-T(PROVENGE®, Dendreon/Valeant Pharmaceuticals), which has been approvedfor treatment of asymptomatic, or minimally symptomatic metastaticcastrate-resistant (hormone-refractory) prostate cancer; and talimogenelaherparepvec (IMLYGIC®, BioVex/Amgen, previously known as T-VEC), agenetically modified oncolytic viral therapy approved for treatment ofunresectable cutaneous, subcutaneous and nodal lesions in melanoma. Insome embodiments, an immuno-oncology agent is selected from an oncolyticviral therapy such as pexastimogene devacirepvec (PexaVec/JX-594,SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-)deficient vaccinia virus engineered to express GM-CSF, forhepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312);pelareorep (REOLYSIN®, Oncolytics Biotech), a variant of respiratoryenteric orphan virus (reovirus) which does not replicate in cells thatare not RAS-activated, in numerous cancers, including colorectal cancer(NCT01622543); prostate cancer (NCT01619813); head and neck squamouscell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); andnon-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev(NG-348, PsiOxus, formerly known as ColoAd1), an adenovirus engineeredto express a full length CD80 and an antibody fragment specific for theT-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastaticor advanced epithelial tumors such as in colorectal cancer, bladdercancer, head and neck squamous cell carcinoma and salivary gland cancer(NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirusengineered to express GM-CSF, in melanoma (NCT03003676); and peritonealdisease, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1(GLV-1 h68/GLV-1 h153, Genelux GmbH), vaccinia viruses engineered toexpress beta-galactosidase (beta-gal)/beta-glucoronidase orbeta-gal/human sodium iodide symporter (hNIS), respectively, werestudied in peritoneal carcinomatosis (NCT01443260); fallopian tubecancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), anadenovirus engineered to express GM-CSF, in bladder cancer(NCT02365818).

In some embodiments, an immuno-oncology agent is selected from JX-929(SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growthfactor-deficient vaccinia virus engineered to express cytosinedeaminase, which is able to convert the prodrug 5-fluorocytosine to thecytotoxic drug 5-fluorouracil; TG01 and TGO2 (Targovax/formerly Oncos),peptide-based immunotherapy agents targeted for difficult-to-treat RASmutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirusdesignated: Ad5/3-E2F-delta24-hTNFα-IRES-hIL20; and VSV-GP(ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered toexpress the glycoprotein (GP) of lymphocytic choriomeningitis virus(LCMV), which can be further engineered to express antigens designed toraise an antigen-specific CD8⁺ T cell response.

In some embodiments, an immuno-oncology agent is a T-cell engineered toexpress a chimeric antigen receptor, or CAR. The T-cells engineered toexpress such chimeric antigen receptor are referred to as a CAR-T cells.

CARs have been constructed that consist of binding domains, which may bederived from natural ligands, single chain variable fragments (scFv)derived from monoclonal antibodies specific for cell-surface antigens,fused to endodomains that are the functional end of the T-cell receptor(TCR), such as the CD3-zeta signaling domain from TCRs, which is capableof generating an activation signal in T lymphocytes. Upon antigenbinding, such CARs link to endogenous signaling pathways in the effectorcell and generate activating signals similar to those initiated by theTCR complex.

For example, in some embodiments the CAR-T cell is one of thosedescribed in U.S. Pat. No. 8,906,682 (June et al.; hereby incorporatedby reference in its entirety), which discloses CAR-T cells engineered tocomprise an extracellular domain having an antigen binding domain (suchas a domain that binds to CD19), fused to an intracellular signalingdomain of the T cell antigen receptor complex zeta chain (such as CD3zeta). When expressed in the T cell, the CAR is able to redirect antigenrecognition based on the antigen binding specificity. In the case ofCD19, the antigen is expressed on malignant B cells. Over 200 clinicaltrials are currently in progress employing CAR-T in a wide range ofindications.[https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=1].

In some embodiments, an immunostimulatory agent is an activator ofretinoic acid receptor-related orphan receptor γ (RORγt). RORγt is atranscription factor with key roles in the differentiation andmaintenance of Type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) Tcells, as well as the differentiation of IL-17 expressing innate immunecell subpopulations such as NK cells. In some embodiments, an activatorof RORγt is LYC-55716 (Lycera), which is currently being evaluated inclinical trials for the treatment of solid tumors (NCT02929862).

In some embodiments, an immunostimulatory agent is an agonist oractivator of a toll-like receptor (TLR). Suitable activators of TLRsinclude an agonist or activator of TLR9 such as SD-101 (Dynavax). SD-101is an immunostimulatory CpG which is being studied for B-cell,follicular and other lymphomas (NCT02254772). Agonists or activators ofTLR8 which may be used in the present invention include motolimod(VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamouscell cancer of the head and neck (NCT02124850) and ovarian cancer(NCT02431559).

Other immuno-oncology agents that can be used in the present inventioninclude urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), ananti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), ananti-OX40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, InnatePharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody;monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2Amonoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), ananti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonalantibody.

In some embodiments, an immunostimulatory agent is selected fromelotuzumab, mifamurtide, an agonist or activator of a toll-likereceptor, and an activator of RORγt.

In some embodiments, an immunostimulatory therapeutic is recombinanthuman interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic asa therapy for melanoma and renal cell carcinoma (NCT01021059 andNCT01369888) and leukemias (NCT02689453). In some embodiments, animmunostimulatory agent is recombinant human interleukin 12 (rhIL-12).In some embodiments, an IL-15 based immunotherapeutic is heterodimericIL-15 (hetlL-15, Novartis/Admune), a fusion complex composed of asynthetic form of endogenous IL-15 complexed to the soluble IL-15binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which hasbeen tested in Phase 1 clinical trials for melanoma, renal cellcarcinoma, non-small cell lung cancer and head and neck squamous cellcarcinoma (NCT02452268). In some embodiments, a recombinant humaninterleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724,or NCT02542124.

In some embodiments, an immuno-oncology agent is selected from thosedescripted in Jerry L. Adams et al., “Big opportunities for smallmolecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pages603-622, the content of which is incorporated herein by refenrece in itsentirety. In some embodimetne, an immuno-oncology agent is selected fromthe examples described in Table 1 of Jerry L. Adams et al. In someembodiments, an immuno-oncology agent is a small molecule targeting animmuno-oncoloby target selected from those listed in Table 2 of Jerry L.Adams et al. In some embodiments, an immuno-oncology agent is a smallmolecule agent selectd from those listed in Table 2 of Jerry L. Adams etal.

In some embodiments, an immuno-oncology agent is selected from the smallmolecule immuno-oncology agents described in Peter L. Toogood, “Smallmolecule immuno-oncology therapeutic agents,” Bioorganic & MedicinalChemistry Letters 2018, Vol. 28, pages 319-329, the content of which isincorporated herein by refenrece in its entirety. In some embodiments,an immuno-oncology agent is an agent targeting the pathways as describedin Peter L. Toogood.

In some embodiments, an immuno-oncology agent is selected from thosedescribed in Sandra L. Ross et al., “Bispecific T cell engager (BITE®)antibody constructs can mediate bystander tumor cell killing”, PLoS ONE12(8): e0183390, the conten of which is incorporated herein by referencein its entirety. In some embodiments, an immuno-oncology agent is abispecific T cell engager (BITE®) antibody construct. In someembodimens, a bispecific T cell engager (BITE®) antibody construct is aCD19/CD3 bispecific antibody construct. In some embodimens, a bispecificT cell engager (BITE®) antibody construct is an EGFR/CD3 bispecificantibody construct. In some embodimens, a bispecific T cell engager(BITE®) antibody construct activates T cells. In some embodimens, abispecific T cell engager (BITE®) antibody construct activates T cells,which release cytokines inducing upregulation of intercellular adhesionmolecule 1 (ICAM-1) and FAS on bystander cells. In some embodimens, abispecific T cell engager (BITE®) antibody construct activates T cellswhich result in induced bystander cell lysis. In some embodiments, thebystander cells are in solid tumors. In some embodiments, the bystandercells being lysed are in proximity to the BITE®-acticvated T cells. Insome embodiment, the bystander cells comprises tumor-associated antigen(TAA) negatgive cancer cells. In some embodiment, the bystander cellscomprise EGFR-negative cancer cells. In some embodiments, animmuno-oncology agent is an antibody which blocks the PD-L1/PD1 axisand/or CTLA4. In some embodiments, an immuno-oncology agent is an exvivo expanded tumor-infiltrating T cell. In some embodiments, animmuno-oncology agent is a bispecific antibody construct or chimericantigen receptors (CARs) that directly connect T cells withtumor-associated surface antigens (TAAs).

Exemplary Immune Checkpoint Inhibitors

In some embodiments, an immuno-oncology agent is an immune checkpointinhibitor as described herein.

The term “checkpoint inhibitor” as used herein relates to agents usefulin preventing cancer cells from avoiding the immune system of thepatient. One of the major mechanisms of anti-tumor immunity subversionis known as “T-cell exhaustion,” which results from chronic exposure toantigens that has led to up-regulation of inhibitory receptors. Theseinhibitory receptors serve as immune checkpoints in order to preventuncontrolled immune reactions.

PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cellImmunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3(Lag-3; CD223), and others are often referred to as a checkpointregulators. They act as molecular “gatekeepers” that allow extracellularinformation to dictate whether cell cycle progression and otherintracellular signaling processes should proceed.

In some embodiments, an immune checkpoint inhibitor is an antibody toPD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) toprevent the receptor from binding to the inhibitory ligand PDL-1, thusoverriding the ability of tumors to suppress the host anti-tumor immuneresponse.

In some embodiments, the checkpoint inhibitor is a biologic therapeuticor a small molecule. In some embodiments, the checkpoint inhibitor is amonoclonal antibody, a humanized antibody, a fully human antibody, afusion protein or a combination thereof. In some embodiments, thecheckpoint inhibitor inhibits a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In some embodiments, the checkpoint inhibitorinteracts with a ligand of a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In some embodiments, the checkpoint inhibitor is animmunostimulatory agent, a T cell growth factor, an interleukin, anantibody, a vaccine or a combination thereof. In some embodiments, theinterleukin is IL-7 or IL-15. In some embodiments, the interleukin isglycosylated IL-7. In an additional aspect, the vaccine is a dendriticcell (DC) vaccine.

Checkpoint inhibitors include any agent that blocks or inhibits in astatistically significant manner, the inhibitory pathways of the immunesystem. Such inhibitors can include small molecule inhibitors or caninclude antibodies, or antigen binding fragments thereof, that bind toand block or inhibit immune checkpoint receptors or antibodies that bindto and block or inhibit immune checkpoint receptor ligands. Illustrativecheckpoint molecules that can be targeted for blocking or inhibitioninclude, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4,BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 familyof molecules and is expressed on all NK, γδ, and memory CD8⁺(4) Tcells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2kinases, A2aR, and various B-7 family ligands. B7 family ligandsinclude, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3,B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies,or antigen binding fragments thereof, other binding proteins, biologictherapeutics, or small molecules, that bind to and block or inhibit theactivity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3,GALS, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative immunecheckpoint inhibitors include, but are not limited to, Tremelimumab(CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal Antibody(Anti-B7-H1; MEDI4736), MK-3475 (PD-1 blocker), Nivolumab (anti-PD1antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224(anti-PDL1 antibody), BMS-936559 (anti-PDL1 antibody), MPLDL3280A(anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody), and ipilimumab(anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include,but are not limited to PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86 and TIM-3.

In certain embodiments, the immune checkpoint inhibitor is selected froma PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In someembodiments, the checkpoint inhibitor is selected from the groupconsisting of nivolumab (OPDIVO®), ipilimumab (YERVOY®), andpembrolizumab (KEYTRUDA®). In some embodiments, the checkpoint inhibitoris selected from nivolumab (anti-PD-1 antibody, OPDIVO®, Bristol-MyersSquibb); pembrolizumab (anti-PD-1 antibody, KEYTRUDA®, Merck);ipilimumab (anti-CTLA-4 antibody, YERVOY®, Bristol-Myers Squibb);durvalumab (anti-PD-L1 antibody, IMFINZI®, AstraZeneca); andatezolizumab (anti-PD-L1 antibody, TECENTRIQ®, Genentech).

In some embodiments, the checkpoint inhibitor is selected from the groupconsisting of lambrolizumab (MK-3475), nivolumab (BMS-936558),pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A,BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (KEYTRUDA®),and tremelimumab.

In some embodiments, an immune checkpoint inhibitor is REGN2810(Regeneron), an anti-PD-1 antibody tested in patients with basal cellcarcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cellcarcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma(NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibodythat binds to PD-1, in clinical trials for diffuse large B-cell lymphomaand multiple myeloma; avelumab (BAVENCIO®, Pfizer/Merck KGaA), alsoknown as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody, inclinical trials for non-small cell lung cancer, Merkel cell carcinoma,mesothelioma, solid tumors, renal cancer, ovarian cancer, bladdercancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis),an inhibitory antibody that binds to PD-1, in clinical trials fornon-small cell lung cancer, melanoma, triple negative breast cancer andadvanced or metastatic solid tumors. Tremelimumab (CP-675,206;Astrazeneca) is a fully human monoclonal antibody against CTLA-4 thathas been in studied in clinical trials for a number of indications,including: mesothelioma, colorectal cancer, kidney cancer, breastcancer, lung cancer and non-small cell lung cancer, pancreatic ductaladenocarcinoma, pancreatic cancer, germ cell cancer, squamous cellcancer of the head and neck, hepatocellular carcinoma, prostate cancer,endometrial cancer, metastatic cancer in the liver, liver cancer, largeB-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplasticthyroid cancer, urothelial cancer, fallopian tube cancer, multiplemyeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884(Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1clinical trials for advanced solid tumors (NCT02694822).

In some embodiments, a checkpoint inhibitor is an inhibitor of T-cellimmunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors thatmay be used in the present invention include TSR-022, LY3321367 andMBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody which is beingstudied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is ananti-TIM-3 antibody which is being studied in solid tumors(NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody which isbeing studied in advanced malignancies (NCT02608268).

In some embodiments, a checkpoint inhibitor is an inhibitor of T cellimmunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor oncertain T cells and NK cells. TIGIT inhibitors that may be used in thepresent invention include BMS-986207 (Bristol-Myers Squibb), ananti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); andanti-TIGIT monoclonal antibody (NCT03119428).

In some embodiments, a checkpoint inhibitor is an inhibitor ofLymphocyte Activation Gene-3 (LAG-3). LAG-3 inhibitors that may be usedin the present invention include BMS-986016 and REGN3767 and IMP321.BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is beingstudied in glioblastoma and gliosarcoma (NCT02658981). REGN3767(Regeneron), is also an anti-LAG-3 antibody, and is being studied inmalignancies (NCT03005782). IMP321 (Immutep S.A.) is an LAG-3-Ig fusionprotein, being studied in melanoma (NCT02676869); adenocarcinoma(NCT02614833); and metastatic breast cancer (NCT00349934).

Checkpoint inhibitors that can be used in the present invention includeOX40 agonists. OX40 agonists that are being studied in clinical trialsinclude PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40 antibody,in metastatic kidney cancer (NCT03092856) and advanced cancers andneoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonisticanti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562(Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, in advancedsolid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonisticanti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectalcancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer(NCT02274155) and metastatic prostate cancer (NCT01303705); andBMS-986178 (Bristol-Myers Squibb) an agonistic anti-OX40 antibody, inadvanced cancers (NCT02737475).

Checkpoint inhibitors that can be used in the present invention includeCD137 (also called 4-1BB) agonists. CD137 agonists that are beingstudied in clinical trials include utomilumab (PF-05082566, Pfizer) anagonistic anti-CD137 antibody, in diffuse large B-cell lymphoma(NCT02951156) and in advanced cancers and neoplasms (NCT02554812 andNCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonisticanti-CD137 antibody, in melanoma and skin cancer (NCT02652455) andglioblastoma and gliosarcoma (NCT02658981); and CTX-471 (CompassTherapeutics), an agonistic anti-CD137 antibody in metastatic or locallyadvanced malignancies (NCT03881488).

Checkpoint inhibitors that can be used in the present invention includeCD27 agonists. CD27 agonists that are being studied in clinical trialsinclude varlilumab (CDX-1127, Celldex Therapeutics) an agonisticanti-CD27 antibody, in squamous cell head and neck cancer, ovariancarcinoma, colorectal cancer, renal cell cancer, and glioblastoma(NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma(NCT02924038).

Checkpoint inhibitors that can be used in the present invention includeglucocorticoid-induced tumor necrosis factor receptor (GITR) agonists.GITR agonists that are being studied in clinical trials include TRX518(Leap Therapeutics), an agonistic anti-GITR antibody, in malignantmelanoma and other malignant solid tumors (NCT01239134 and NCT02628574);GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors andlymphoma (NCT 02740270); INCAGN01876 (Incyte/Agenus), an agonisticanti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110);MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors(NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistichexameric GITR-ligand molecule with a human IgG1 Fc domain, in advancedsolid tumors (NCT02583165).

Checkpoint inhibitors that can be used in the present invention includeinducible T-cell co-stimulator (ICOS, also known as CD278) agonists.ICOS agonists that are being studied in clinical trials include MEDI-570(Medimmune), an agonistic anti-ICOS antibody, in lymphomas(NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, inPhase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonisticanti-ICOS antibody, in Phase 1 (NCT02904226).

Checkpoint inhibitors that can be used in the present invention includekiller IgG-like receptor (KIR) inhibitors. KIR inhibitors that are beingstudied in clinical trials include lirilumab (IPH2102/BMS-986015, InnatePharma/Bristol-Myers Squibb), an anti-KIR antibody, in leukemias(NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma(NCT02252263), and lymphoma (NCT01592370); IPH2101 (I-7F9, InnatePharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (InnatePharma), an anti-KIR antibody that binds to three domains of the longcytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).

Checkpoint inhibitors that can be used in the present invention includeCD47 inhibitors of interaction between CD47 and signal regulatoryprotein alpha (SIRPa). CD47/SIRPa inhibitors that are being studied inclinical trials include ALX-148 (Alexo Therapeutics), an antagonisticvariant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediatedsignaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, TrilliumTherapeutics), a soluble recombinant fusion protein created by linkingthe N-terminal CD47-binding domain of SIRPa with the Fc domain of humanIgG1, acts by binding human CD47, and preventing it from delivering its“do not eat” signal to macrophages, is in clinical trials in Phase 1(NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47antibody, in leukemias (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.),in colorectal neoplasms and solid tumors (NCT02953782), acute myeloidleukemia (NCT02678338) and lymphoma (NCT02953509).

Checkpoint inhibitors that can be used in the present invention includeCD73 inhibitors. CD73 inhibitors that are being studied in clinicaltrials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solidtumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), ananti-CD73 antibody, in solid tumors (NCT02754141).

Checkpoint inhibitors that can be used in the present invention includeagonists of stimulator of interferon genes protein (STING, also known astransmembrane protein 173, or TMEM173). Agonists of STING that are beingstudied in clinical trials include MK-1454 (Merck), an agonisticsynthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100(MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclicdinucleotide, in Phase 1 (NCT02675439 and NCT03172936).

Checkpoint inhibitors that can be used in the present invention includeCSF1R inhibitors. CSF1R inhibitors that are being studied in clinicaltrials include pexidartinib (PLX3397, Plexxikon), a CSF1R small moleculeinhibitor, in colorectal cancer, pancreatic cancer, metastatic andadvanced cancers (NCT02777710) and melanoma, non-small cell lung cancer,squamous cell head and neck cancer, gastrointestinal stromal tumor(GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly),an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma(NCT03101254), and solid tumors (NCT02718911); and BLZ945(4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylicacid methylamide, Novartis), an orally available inhibitor of CSF1R, inadvanced solid tumors (NCT02829723).

Checkpoint inhibitors that can be used in the present invention includeNKG2A receptor inhibitors. NKG2A receptor inhibitors that are beingstudied in clinical trials include monalizumab (IPH2201, Innate Pharma),an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) andchronic lymphocytic leukemia (NCT02557516).

In some embodiments, the immune checkpoint inhibitor is selected fromnivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab,atezolizumab, or pidilizumab.

A compound of the current invention may also be used in combination withknown therapeutic processes, for example, the administration of hormonesor radiation. In certain embodiments, a provided compound is used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

A compound of the current invention can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic compounds being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic compounds. A compound of the current inventioncan besides or in addition be administered especially for tumor therapyin combination with chemotherapy, radiotherapy, immunotherapy,phototherapy, surgical intervention, or a combination of these.Long-term therapy is equally possible as is adjuvant therapy in thecontext of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of the currentinvention, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive compound can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically. Therefore, the amount of additional therapeuticagent in such compositions will be less than that required in amonotherapy utilizing only that therapeutic agent. In such compositionsa dosage of between 0.01-1,000 μg/kg body weight/day of the additionaltherapeutic agent can be administered.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention, or pharmaceutical compositions thereof,may also be incorporated into compositions for coating an implantablemedical device, such as prostheses, artificial valves, vascular grafts,stents and catheters. Vascular stents, for example, have been used toovercome restenosis (re-narrowing of the vessel wall after injury).However, patients using stents or other implantable devices risk clotformation or platelet activation. These unwanted effects may beprevented or mitigated by pre-coating the device with a pharmaceuticallyacceptable composition comprising a kinase inhibitor. Implantabledevices coated with a compound of this invention are another embodimentof the present invention.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein. Additional compounds of theinvention were prepared by methods substantially similar to thosedescribed herein in the Examples and methods known to one skilled in theart.

Synthesis of Intermediates Synthesis of tert-butyl4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1)

Step-1 Synthesis of tert-butyl4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1-1)

To a solution of 5-bromo-2-nitropyridine (3.0 g 14.76 mmol, 1.0 eq.) andtert-butyl piperazine-1-carboxylate (4.2 g 22.58 mmol, 1.5 eq.) in dryDMSO (10.0 mL) was added triethylamine (2.25 g, 22.27 mmol, 1.5 eq.) andlithium chloride (0.63 g,14.76 mmol,1.0 eq.) at RT. The reaction mixturewas heated at 70° C. for 20 h. After completion of reaction, thereaction mixture was poured into ice water and solid product wascollected by filtration. Solid was triturated with n-pentane to affordIntermediate AA1-1 (3.0 g, 65.84%) MS (ES) m/z 309.33 (M+H)⁺.

Step-2 Synthesis of tert-butyl4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. (Intermediate AA1)

To a suspension of 10% Pd/C (2.2 g) in methanol (50 mL) was added asolution of Intermediate AA1-1 (4.0 g, 12.98 mmol) in methanol (10 mL)under nitrogen atmosphere. H2 (gas) was bubbled into the reactionmixture for 3 h. After completion of reaction, the reaction mixture wasfiltered through celite and washed with methanol. The filtrate wasconcentrated under reduced pressure to give Intermediate AA1 (2.4 g,55.39%). MS (ES): m/z 279.24 [M+H]⁺.

Synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine (IntermediateAA2)

Step-1 Synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine(Intermediate AA2)

5-(4-methylpiperazin-1-yl)pyridin-2-amine (Intermediate AA2) wasprepared from 5-bromo-2-nitropyridine (Intermediate AA1-1) and1-methylpiperazine in a similar fashion to that described in tert-butyl4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. (General processIntermediate AA1) (1.0 g, 70.84%) MS (ES) m/z 193.2 (M+H)⁺.

Synthesis of 5-morpholinopyridin-2-amine (Intermediate AA3)

Step-1 Synthesis of 5-morpholinopyridin-2-amine (Intermediate AA3)

5-morpholinopyridin-2-amine (Intermediate AA3) was prepared from5-bromo-2-nitropyridine (Intermediate AA3-1) and morpholine in a similarfashion to that described in tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. (General process Intermediate AA1). (1.0 g,64.84%) MS (ES) m/z 180.33 (M+H)⁺.

Synthesis of tert-butyl3-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(Intermediate AA6)

Step-1 Synthesis of tert-butyl3-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.(Intermediate AA6-1)

To a solution of 5-bromo-2-nitropyridine (Intermediate AA1-1) (1.0 g 4.9mmol, 1.0 eq.) in 1,4-dioxane (13.0 mL) were added tert-butyl3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.05 g, 4.9 mmol, 1.0 eq.)and tripotassium phosphate (2.03 g, 14.7 mmol, 3.0 eq.) at RT. Afterdegassing with argon for 20 min, Pd₂dba₃ (0.45 g, 0.49 mmol, 0.1 eq.)and xantphos (0.57 g, 0.98 mmol, 0.2 eq.) were added to the reactionmixture. After heating at 120° C. for 3 h, the reaction mixture waspoured into water (100 mL) and extracted with ethyl acetate (100 mL×3).The organic layer was washed with brine (100 mL) solution, dried oversodium sulfate, and concentrated under reduced pressure which. The crudecompound was purified by column chromatography (0-40% gradient elutionEtOAc in Hexanes) to afford the title compound (Intermediate AA6-1)(0.500 g, 30.35%). MS (ES): m/z 334.3 (M+H)⁺.

Step-2 Synthesis of tert-butyl3-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(Intermediate AA6)

tert-butyl3-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(Intermediate AA6) in a similar fashion to that described tert-butyl4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. (General processIntermediate AA1) (0.430 g, 94.4%). MS (ES): m/z 304 (M+H)⁺.

Synthesis of 1-(6-amino-5-methoxypyridin-3-yl)piperidin-4-ol(Intermediate AA7)

Step-1 Synthesis of 1-(5-methoxy-6-nitropyridin-3-yl)piperidin-4-ol(Intermediate AA7-2)

To a solution of 5-bromo-3-methoxy-2-nitropyridine (Intermediate AA7-1)(0.5 g 2.1 mmol, 1.0 eq.) in dry DMSO (6 mL) was added piperidin-4-ol(0.35 g, 2.6 mmol, 1.2 eq.), potassium carbonate (1.7 g, 12.0 mmol, 6.0eq.) and tetrabutylammonium iodide (0.22 g, 0.6 mmol, 0.3 eq.) at RT.After heating at 90° C. for 2 h, the reaction mixture was poured intowater (100 mL) and extracted with ethyl acetate (100×3). The organiclayer was washed with brine (100 mL) solution, dried over sodiumsulfate, and concentrated under reduced pressure. The crude compound waspurified by column chromatography (0-40% gradient elution EtOAc inHexanes) to afford the title compound (Intermediate AA7-1) (0.3 g,56.24%). MS (ES): m/z 254.2 (M+H)⁺.

Step-2 Synthesis of 1-(6-amino-5-methoxypyridin-3-yl)piperidin-4-ol(Intermediate AA7)

1-(6-amino-5-methoxypyridin-3-yl)piperidin-4-ol (Intermediate AA7) wasprepared in a similar fashion to that described tert-butyl4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. (General processIntermediate AA1). (0.2 g, 74.73%). MS (ES): m/z 224.2 (M+H)⁺.

Synthesis of tert-butyl4-(6-aminopyridin-3-yl)-4-methylpiperidine-1-carboxylate (IntermediateAA9)

Step-1 Synthesis of ethyl(E)-3-(6-chloropyridin-3-yl)-2-cyanobut-2-enoate (Intermediate AA9-2)

To a solution of 1-(6-chloropyridin-3-yl)ethan-1-one (10.0 g 64.51 mmol,1.0 eq.) and ethyl 2-cyanoacetate (7.2 g 64.51 mmol, 1.0 eq.) in toluene(35 mL) were added ammonium acetate (1.0 g, 12.90 mmol, 0.2 eq) andacetic acid (4 mL). After stirring at 140° C. for 6 h in dean starkassembly, the reaction mixture was diluted with sodium bicarbonatesolution (150 mL) and extracted with ethyl acetate (2×100 mL). Thecombined organic extracts were washed with brine (200 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure to affordcrude material. This material was used in next Step withoutpurification. Intermediate AA9-2 (15.0 g, 96.09%) MS (ES) m/z 251.05(M+H)⁺.

Step-2 Synthesis of4-(6-chloropyridin-3-yl)-4-methyl-2,6-dioxopiperidine-3,5-dicarbonitrile(Intermediate AA9-3)

To a solution of Intermediate AA9-2 (14.9 g, 59.6 mmol) and2-cyanoacetamide (6.0 g, 71.52 mmol, 1.2 eq) in ethanol (130 mL) wasadded sodium hydroxide (2.86 g, 71.52 mmol, 1.2 eq). The reactionmixture was stirred at RT for 1 h. After completion of reaction, 1M ofpotassium bisulfate solution was added to the reaction mixture. Afterstirring at 10° C., a solid precipitated from solution. The solid wasfiltered and dried under high vacuum to afford Intermediate AA9-3 whichwas used in next Step without purification. (20.0 g, 98.12%). MS (ES):m/z 289.04 [M+H]⁺

Step-3 Synthesis of4-(6-chloropyridin-3-yl)-4-methylpiperidine-2,6-dione (IntermediateAA9-4)

To a solution of Intermediate AA9-3 (20.0 g, 69.44 mmol) in Water (12mL) was added dropwise sulfuric acid (12 mL) at 10° C. After stirring at110° C. for 7 h, solid sodium hydroxide was added at 0° C. The reactionmixture was filtered and washed with 10% methanol in DCM. The combinedorganic layer was dried over sodium sulfate and concentrated underreduced pressure to afford liquid material. Urea (40 g) was added tothis crude material and stirred at 140° C. for 2 h. The reaction mixturewas diluted with ethyl acetate (1 L) and saturated sodium bicarbonatesolution (500 mL). The organic layer was collected, washed with brinesolution (300 mL), dried over sodium sulfate and concentrated underreduced pressure to afford Intermediate AA9-4 which was used in nextStep without purification. (2.2 g, 13.31%). MS (ES): m/z 239.05 [M+H]⁺

Step-4 Synthesis of1-benzyl-4-(6-chloropyridin-3-yl)-4-methylpiperidine-2,6-dione(Intermediate AA9-5)

To a solution of Intermediate AA9-4 (1.2 g, 5.02 mmol) in acetone (50mL) was added potassium carbonate (1.38 g, 10.04 mmol, 2.0 eq) andstirred at 0° C. Benzyl bromide (0.94 g, 5.52 mmol, 1.1 eq) was addedinto the reaction mixture and then stirred at 70° C. for 2 h. Aftercompletion of reaction, the reaction mixture distilled out to removeacetone. The residue was diluted with water (150 mL) and extracted withethyl acetate (70 mL×3). The combined organic layer washed with brinesolution, dried over sodium sulfate, and concentrated under reducedpressure to afford crude material. The residue was purified by columnchromatography eluting with 25% ethyl acetate in hexane to affordIntermediate AA9-5. (1.5 g, 90.74%). MS (ES): m/z 329.10 [M+H]⁺

Step-5 Synthesis of 5-(1-benzyl-4-methylpiperidin-4-yl)-2-chloropyridine(Intermediate AA9-6)

To a solution of Intermediate AA9-5 (1.2 g, 3.65 mmol) in dry THF (20mL) was added lithium aluminum hydride (1.0M in THF) (14 mL, 14.06 mmol,4.0 eq) at −5° C. After stirring at 70° C. for 1 h, reaction mixture wasconcentrated. The reside was diluted with water (100 mL) and extractedwith ethyl acetate (50 mL×3). The combined organic layer washed withbrine solution, dried over sodium sulfate, and concentrated underreduced pressure to afford crude material. This material was purified bycolumn chromatography eluting with 1.2% ethyl acetate in hexane toafford Intermediate AA9-6. (0.4 g, 36.43%). MS (ES): m/z 301.2 [M+H]⁺

Step-6 Synthesis ofN-(5-(1-benzyl-4-methylpiperidin-4-yl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA9-7)

A solution of Intermediate AA9-6. (1.6 g, 5.33 mmol)cyclopropanecarboxamide (0.679 g, 7.99 mmol, 1.5 eq), and cesiumcarbonate (5.1 g, 15.99 mmol, 3.0 eq) in 1,4-dioxane (20 mL) wasdegassed under N2 stream. After 15 min, Xantphos (0.308 g, 0.53 mmol,0.1 eq) and Pd₂(dba)₃ (0.487 g, 0.53 mmol, 0.1 eq) added. After stirringat 120° C. for 16 h, the reaction mixture was cooled to RT, dilutedwater (100 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic extracts were washed with brine (100 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography eluting with 2.5% gradient of methanolin DCM to afford Intermediate AA9-7 (1.6 g, 69.94%) as a brown solid. MS(ES): m/z=350.2 [M+H]⁺

Step-7 Synthesis ofN-(5-(4-methylpiperidin-4-yl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA9-8)

To a solution of Intermediate AA9-7 (0.5 g, 1.43 mmol) in methanol (10mL) was added 10% Pd/C (0.250 g was hydrogenated at atmospheric pressurefor 6 h at RT. After completion of reaction, the reaction mixture wasfiltered through celite-bed and washed with methanol. The filtrate wasconcentrated under reduced pressure to afford crude material which wasused in next Step without purification. Intermediate AA9-8 (0.450 g,94.32%). MS (ES): m/z 260.1 [M+H]⁺,

Step-8 Synthesis of tert-butyl4-(6-(cyclopropanecarboxamido)pyridin-3-yl)-4-methylpiperidine-1-carboxylate(Intermediate AA9-9)

To a solution of Intermediate AA9-8 (0.450 g, 1.73 mmol) in DCM (20 mL)were added trimethylamine (0.524, 5.19 mmol, 3.0 eq) and DMAP (0.021 g,0.173 mmol, 0.1 eq). Di-tert-butyl dicarbonate (0.754, 3.46 mmol, 2.0eq) was then added dropwise into the rection mixture. After stirring atRT for 2 h, the reaction mixture concentrated, diluted with water (50mL), and extracted with ethyl acetate (30 mL×3). The combined organiclayer washed with brine solution, dried over sodium sulfate, andconcentrated under reduced pressure to afford crude material. Theresidue was purified by column chromatography eluting with 2.5% methanolin DCM to afford Intermediate AA9-9. (0.450 g, 72.15%). MS (ES): m/z360.2 [M+H]⁺

Step-9 Synthesis of tert-butyl4-(6-aminopyridin-3-yl)-4-methylpiperidine-1-carboxylate(Intermediate-AA9)

To a solution of Intermediate AA9-9 (0.450 g, 1.25 mmol) in methanol (10mL) was added sodium hydroxide (0.5 g, 12.5 mmol, 10.0 eq). Afterstirring at 50° C. for 16 h, the reaction mixture was poured in water(70 mL) and extracted with DCM (40 mL×3). The combined organic layerwashed with brine solution, dried over sodium sulfate, and concentratedunder reduced pressure to afford crude material. The residue waspurified by column chromatography eluting with 4.0% methanol in DCM toafford Intermediate-AA9 (0.210 g, 57.57%). MS (ES): m/z 292.2 [M+H]⁺

Synthesis of 2-(1-(6-aminopyridin-3-yl)piperidin-3-yl)propan-2-ol(Intermediate AA13)

Step-1 Synthesis of ethyl1-(6-nitropyridin-3-yl)piperidine-3-carboxylate (Intermediate AA13-2)

Ethyl 1-(6-nitropyridin-3-yl)piperidine-3-carboxylate (IntermediateAA13-2) was prepared from 5-bromo-2-nitropyridine (Intermediate AA2-1)and 1-ethyl piperidine-3-carboxylate in a similar fashion to thatdescribed tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate(General process Intermediate AA1). (1.5 g, 36.34%) MS (ES): m/z 280.14[M+H]⁺

Step-2 Synthesis of ethyl1-(6-aminopyridin-3-yl)piperidine-3-carboxylate (Intermediate AA13-3)

Ethyl 1-(6-aminopyridin-3-yl)piperidine-3-carboxylate (IntermediateAA13-3) was prepared from ethyl1-(6-nitropyridin-3-yl)piperidine-3-carboxylate (Intermediate AA13-2) ina similar fashion to that described tert-butyl4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. (General processIntermediate AA1) (1.2 g, 89.62%). MS (ES): m/z 250.15 [M+H]⁺

Step-3 Synthesis of 2-(1-(6-aminopyridin-3-yl)piperidin-3-yl)propan-2-ol(Intermediate AA13)

To a solution of ethyl 1-(6-aminopyridin-3-yl)piperidine-3-carboxylate(Intermediate AA13-3) (2.0 g, 8.03 mmol) in THF (15 mL) was added a 3Nsolution of methyl magnesium bromide (3N in THF) (20 mL) dropwise at 0°C. After stirring at RT for 1 h, the reaction mixture was quenched withice cool water (100 mL) and filtered on celite bed. The filtrate wasextracted with ethyl acetate (100 mL×3). The combine organic layerwashed with brine (100 mL) and concentrated under reduced. The crudecompound was purified by column chromatography (0-80% gradient elutionEtOAc in hexanes) to afford the title compound (Intermediate AA13)(0.200 g, 10.60%). MS (ES): m/z 236.17 [M+H]⁺

Synthesis of5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-2-amine(Intermediate AA14)

Step-1 Synthesis of5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-2-amine(Intermediate AA14)

5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-2-amine(Intermediate AA14) was prepared from 5-bromo-2-nitropyridine(Intermediate AA1-1) and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane in asimilar fashion to that described tert-butyl4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (General processIntermediate AA1). (0.330 g, Quantitative yield). MS (ES): m/z 192.5[M+H]⁺.

Synthesis of 1-(6-bromopyridin-3-yl)-4-(morpholinomethyl)piperidin-4-ol(Intermediate AA15)

Step-1 Synthesis of1-(6-bromopyridin-3-yl)-4-(morpholinomethyl)piperidin-4-ol (IntermediateAA15)

To a solution of 2-bromo-5-iodopyridine (0.6 g, 2.0 mmol) in 1,4-dioxane(6 mL) were added 4-(morpholinomethyl)piperidin-4-ol (0.64 g, 3.0 mmol,1.5 eq) and cesium carbonate (2.1, 6.0 mmol, 3.0 eq). After degassingwith nitrogen gas for 10 min,4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.125 g, 0.02 mmol, 0.1eq) and tris(dibenzylideneacetone)dipalladium (0.2 g, 0.2 mmol, 0.1 eq)were added under nitrogen gas atmosphere. The reaction mixture washeated to 120° c. for 3 h. The reaction mixture was diluted with water(50 mL) and extracted with ethyl acetate (50 mL×3). The combined organiclayer was washed with brine (50 mL) solution, dried over sodium sulfateand concentrated under reduced pressure to afford crude material whichwas purified using combi-flash silica eluting with 4% methanol/DCM toafford Intermediate AA15 (0.2 g, 26.56%) MS (ES): m/z 357.26 [M+H]⁺

Synthesis of 1-(6-chloro-4-methoxypyridin-3-yl)piperidin-4-ol(Intermediate AA18)

Step-1 Synthesis of 6-chloro-4-methoxypyridin-3-amine (IntermediateAA18-2)

To a solution of 2-chloro-4-methoxy-5-nitropyridine (IntermediateAA18-1) (2.0 g, 10.6 mmol) in ethanol (8 mL),) was added SnCl₂.2H₂O (9.6g, 63.8 mmol, 6.0 eq). After stirring at 90° C. for 30 mins, thereaction mixture was quenched with e 3M NaOH solution (100 mL) andextracted with DCM (100 mL). The combined organic layer was washed withbrine solution (100 mL), dried over sodium sulfate and concentratedunder reduced pressure to afford crude material. The residue waspurified by column chromatography eluting with 15-20% ethyl acetate inhexane to afford Intermediate AA18-2. LCMS purity 100%, MS (ES): m/z159.03 [M+H]⁺

Step-2 Synthesis of 1-(6-chloro-4-methoxypyridin-3-yl)piperidin-4-one(Intermediate AA18-3)

To a refluxing slurry of sodium carbonate (1.51 g, 14 mmol, 1.5 eq) inMeOH (8 mL) was added a solution of Intermediate AA18-2 (1.5 g, 9.5mmol) in MeOH (2 mL) and 1,5-dichloropentan-3-one (1.6 g, 9.5 mmol,1.0eq). After stirring at 50° C. for 16 h, the reaction mixture wasconcentrated under vacuum to give crude material that was purified bycolumn chromatography eluting with 20-25% ethyl acetate in hexane toafford Intermediate AA18-3. (1.2 g, 80.01%) MS (ES): 241.07 m/z [M+H]⁺

Step-3 Synthesis of 1-(6-chloro-4-methoxypyridin-3-yl)piperidin-4-ol(Intermediate AA18)

To a solution of Intermediate AA18-3 (1.2 g, 5 mmol) in MeOH (12 mL) wasadded NaBH4 (0.228 g, 6 mmol, 1.2 eq). After stirring for 30 mins, thereaction mixture was diluted with water (50 mL) and extracted with ethylacetate (50 mL×3). The combined organic layer was washed with brine (50mL) solution, dried over sodium sulfate, and concentrated under reducedpressure to afford crude material which was purified using combi-flashsilica eluting with 15-20% ethyl acetate in hexane to affordIntermediate AA18. MS (ES): 243 m/z [M+H]+.

Synthesis of 2-(6-aminopyridin-3-yl)-2-azaspiro[3.3]heptan-6-ol(Intermediate AA19)

Step-1 Synthesis of 2-(6-aminopyridin-3-yl)-2-azaspiro[3.3]heptan-6-ol(Intermediate AA19)

2-(6-aminopyridin-3-yl)-2-azaspiro[3.3]heptan-6-ol (Intermediate AA19)was prepared from 5-bromo-2-nitropyridine (Intermediate AA1-1) and2-azaspiro[3.3]heptan-6-ol in a similar fashion to that describedtert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (Generalprocess intermediate AA1). 0.600 g, 98.23%). MS (ES): m/z 206.12 [M+H]⁺

Synthesis of 1-(6-aminopyridin-3-yl)-4-(methoxymethyl)piperidin-4-ol(Intermediate AA20)

Step-1 Synthesis of1-(6-aminopyridin-3-yl)-4-(methoxymethyl)piperidin-4-ol (IntermediateAA20)

1-(6-aminopyridin-3-yl)-4-(methoxymethyl)piperi din-4-ol (IntermediateAA20) was prepared from 5-bromo-2-nitropyridine (Intermediate AA1-1) and4-(methoxymethyl)piperidin-4-ol in a similar fashion to that describedtert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. (Generalprocess intermediate AA1). (0.600 g, 96.54%). MS (ES): m/z 238.12 [M+H]⁺

Synthesis of 5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-2-amine(Intermediate AA21)

5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-2-amine (Intermediate AA21)was prepared from 5-bromo-2-nitropyridine (Intermediate AA1-1) and2-oxa-7-azaspiro[3.5]nonane in a similar fashion to that describedtert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. (Generalprocess intermediate AA1). (0.3 g, 75.76%). MS (ES): m/z 220.2 (M+H)⁺.

Synthesis of 5-(1,4-oxazepan-4-yl)pyridin-2-amine (Intermediate AA22)

5-(1,4-oxazepan-4-yl)pyridin-2-amine (Intermediate AA22) was preparedfrom 5-bromo-2-nitropyridine (Intermediate AA1-1) and 1,4-oxazepane in asimilar fashion to that described tert-butyl4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. (General processintermediate AA1). (0.300 g, 57.76%). MS (ES): m/z 194.15 [M+H]⁺

Synthesis of(1R,3r,5S)-8-(6-aminopyridin-3-yl)-8-azabicyclo[3.2.1]octan-3-ol(Intermediate AA23)

(1R,3r,5S)-8-(6-aminopyridin-3-yl)-8-azabicyclo[3.2.1]octan-3-ol(Intermediate AA23) was prepared from 5-bromo-2-nitropyridine(Intermediate AA1-1) and (1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-ol in asimilar fashion to that described tert-butyl4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. (General processintermediate AA1) (1.8 g, 94.7%). MS (ES): m/z 219.2 (M+H)⁺.

Synthesis of 5-(azetidin-1-ylsulfonyl)-2-chloropyridine (IntermediateAA25)

Step-1 Synthesis of Intermediate AA25-2

Prepared as described in WO2020/89026.

Step-2 Synthesis of 5-(azetidin-1-ylsulfonyl)-2-chloropyridine(Intermediate AA25)

A solution of 5-(azetidin-1-ylsulfonyl)-2-chloropyridine (IntermediateAA25-2) (400 mg, 1.51 mol) in ammonia solution in water (3000 mL) wasallowed to stir at 80° C. for 16 h. After completion of reaction, thereaction was concentrated under vacuum to afforded title compound aswhite solid (Intermediate AA25) (200 mg, 78.74%). MS (ES): m/z214.59[M+H]⁺

Synthesis of5-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-2-amine(Intermediate AA30)

Step-1: Synthesis of(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(Intermediate AA30-2)

To a solution of 5-fluro-2-nitro pyridine (1.0 g 7.04 mmol, 1.0 eq.) indimethyl sulfoxide (13.0 mL) were added(3aR,6aS)-rel-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride (1.05 g,7.04 mmol,1.0 eq.) and N,N-diisopropylethylamine (10 eq, 70.4 mmol.) atRT. After stirring at 120° C. for 1 h, the reaction mixture was pouredinto water and extracted with ethyl acetate (100 mL×3). The organiclayer was washed with brine (100 mL×3) solution. The combined organiclayer was concentrated under reduced pressure at 45° C. to affordIntermediate AA30-2 (2 g, 172.5%). MS (ES): m/z 236.33 (M+H)⁺.

Step-2 Synthesis of5-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-2-amine(Intermediate AA30)

Synthesis of 5-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-2-amine(Intermediate AA30) was prepared from(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(Intermediate AA30-2) in a similar fashion to that described tert-butyl4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. (General processintermediate AA1). (0.600 g, 96.54%). MS (ES): m/z 238.12 [M+H]⁺

Synthesis of 5-((cyclobutylmethyl)sulfonyl)pyridin-2-amine (IntermediateAA32)

Step-1 Synthesis of 2-chloro-5-((cyclobutylmethyl)sulfonyl)pyridine(Intermediate AA32-2)

To a solution of 6-chloropyridine-3-sulfonyl chloride (2.0 g, 9.43 mmol)in water (40 mL) were added sodium bicarbonate (1.73 g, 9.43 mmol) andsodium sulphite (1.18 g, 9.43 mmo). After stirring at 40° C. for 1 h,the reaction mixture was concentrated by high vacuum to give a solid. Toa solution of the solid in N′N-DMF (20 mL) were added(bromomethyl)cyclobutane (1.68 g, 11.3 mmo, 1.2 eq) and pyridine (0.679g, 11.3 mmo). After stirring at RT for 16 h, the reaction wasconcentrated, diluted with water, and extracted with ethyl acetate (100mL×3). The combined organic layer was washed with brine solution, driedover sodium sulfate and concentrated under reduced pressure to affordcrude material which was purified using Column chromatography elutingwith 15% ethyl acetate/hexane to afford Intermediate AA32-2 (0.900 g,27.29%) MS (ES): m/z 246.03 [M+H]⁺

Step-2 Synthesis of 5-((cyclobutylmethyl)sulfonyl)pyridin-2-amine(Intermediate AA32)

To a solution of methanolic ammonia (5 mL) was added2-chloro-5-((cyclobutylmethyl)sulfonyl)pyridine (0.900 g, 3.65 mmol).After stirring at RT for 16 h, the reaction mixture was diluted in waterand extracted with ethyl acetate. The combined organic solution wasconcentrated under reduced pressure to give crude material. The residuewas purified by column chromatography eluting with 30% ethyl acetate inhexane to give Intermediate AA32 (0.100 g, 12.06%). MS (ES): m/z227.12[M+H]⁺.

Synthesis of 1-(2-aminopyridin-4-yl)piperidin-4-ol (Intermediate AA34)

1-(2-aminopyridin-4-yl)piperidin-4-ol (Intermediate AA34) was preparedfrom 4-chloro-2-nitropyridine (Intermediate AA34-1) and piperidin-4-olin a similar fashion to that described1-(6-amino-5-methoxypyridin-3-yl)piperidin-4-ol (General processIntermediate AA7). 1.37 g, 83.29%). MS (ES): m/z 194.12 [M+H]⁺

Synthesis of 1-(6-aminopyridin-3-yl)azepan-4-ol (Intermediate AA37)

1-(6-aminopyridin-3-yl)azepan-4-ol (Intermediate AA37) was prepared from5-fluoro-2-nitropyridine (Intermediate AA30-1) and azepan-4-ol in asimilar fashion to that described in 5-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-2-amine(General process Intermediate AA30) (0.500 g, 81.76%). MS (ES): m/z208.14[M+H]⁺

Synthesis of 5-(2-(methoxymethyl)morpholino)pyridin-2-amine(Intermediate AA39)

5-(2-(methoxymethyl)morpholino)pyridin-2-amine (Intermediate AA37) wasprepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and2-(methoxymethyl)morpholine in a similar fashion to that described in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process Intermediate AA30). (0.700 g, 79.4%). MS (ES): m/z224.14[M+H]⁺

Synthesis of 4-(6-aminopyridin-3-yl)-1,4-oxazepan-6-ol (IntermediateAA43)

4-(6-aminopyridin-3-yl)-1,4-oxazepan-6-ol (Intermediate AA43) wasprepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and1,4-oxazepan-6-ol in a similar fashion to that described in 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Generalprocess Intermediate AA30). (0.7 g, 61.56%). MS (ES): m/z 210.26 [M+H]⁺

Synthesis of (S)-2-(4-(6-aminopyridin-3-yl)morpholin-2-yl)propan-2-ol(Intermediate AA48)

(S)-2-(4-(6-aminopyridin-3-yl)morpholin-2-yl)propan-2-ol (IntermediateAA43) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1)and (S)-2-(morpholin-2-yl)propan-2-ol in a similar fashion to thatdescribed in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (0.7 g, 61.56%). (4 g, 75%). MS(ES): m/z 237.15 [M+H]⁺

Synthesis of ((3R,4R)-1-(6-aminopyridin-3-yl)-4-fluoropiperidin-3-ol(Intermediate AA49)

((3R,4R)-1-(6-aminopyridin-3-yl)-4-fluoropiperidin-3-ol (IntermediateAA49) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1)and (3R,4R)-4-fluoropiperidin-3-ol in a similar fashion to thatdescribed in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (0.500 g, 63.44%). MS (ES): m/z212.11 [M+H]⁺

Synthesis of 1-(6-aminopyridin-3-yl)-2-methylpiperidin-4-ol(Intermediate AA50)

1-(6-aminopyridin-3-yl)-2-methylpiperidin-4-ol (Intermediate AA50) wasprepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and2-methylpiperidin-4-ol in a similar fashion to that described in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (0.900 gm, 93.75%) MS (ES): m/z 207[M+H]⁺

Synthesis of (1R,2S)-2-((6-aminopyridin-2-yl)oxy)cyclopentan-1-ol(Intermediate AA51)

Step-1 Synthesis of (1R,2S)-2((6-nitropyridin-2-yl)oxy)cyclopentan-1-ol(Intermediate AA51-2)

To a solution of 2-chloro-6-nitropyridine (3.0 g 18.98 mmol, 1.0 eq.)and (1R,2S)-cyclopentane-1,2-diol (2.3 g 22.77 mmol, 1.2 eq.) in dry DMF(36 mL) was added potassium carbonate (7.8 g, 56.94 mmol, 3.0 eq) at RT.After stirring at 120° C. for 16 h, the reaction mixture was poured intoice water and extracted with ethyl acetate (2×120 mL). The combinedorganic extracts were washed with brine (100 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure to afford crudematerial. The residue was purified by column chromatography eluting with3.0% ethyl acetate gradient in hexane to afford Intermediate AA51-2(0.330 g, 8.0%) MS (ES) m/z 225.08 (M+H)⁺.

Step-2 Synthesis of (1R,2S)-2-((6-aminopyridin-2-yl)oxy)cyclopentan-1-ol(Intermediate AA51)

To a suspension of Intermediate AA51-2 (0.3 g, 1.33 mmol) in methanol(10 mL) was added 10% Pd/C (0.250 g) was hydrogenated at atmosphericpressure for 6 h at RT. After completion of reaction, the reactionmixture was filtered through celite-bed and washed with methanol. Thefiltrate was concentrated under reduced pressure to afford crudematerial which was used in next Step without purification. IntermediateAA51 (0.268 g, 98.12%). MS (ES): m/z 195.1 [M+H]⁺,

Synthesis of 1-(1-(6-aminopyridin-3-yl)piperidin-3-yl)ethan-1-ol(Intermediate AA52)

1-(1-(6-aminopyridin-3-yl)piperidin-3-yl)ethan-1-ol (Intermediate AA52)was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and2-methylpiperidin-4-ol in a similar fashion to that described in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (1.1 gm, 78.6%) MS (ES): m/z 222.1[M+H]⁺

Synthesis of (3R,4S)-1-(6-aminopyridin-3-yl)-4-fluoropiperidin-3-ol(Intermediate AA54)

((3R,4S)-1-(6-aminopyridin-3-yl)-4-fluoropiperidin-3-ol (IntermediateAA54) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1)and (3R,4S)-4-fluoropiperidin-3-ol in a similar fashion to thatdescribed in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (1.0 g, 76.13%). MS (ES): m/z212.11 [M+H]⁺

Synthesis of1-(6-aminopyridin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)piperidin-4-ol(Intermediate AA55)

1-(6-aminopyridin-3-yl)-4-(4-methylpiperazin-1-yl)methyl)piperidin-4-ol(Intermediate AA55) was prepared from 5-fluoro-2-nitropyridine(Intermediate AA30-1) and4-((4-methylpiperazin-1-yl)methyl)piperidin-4-ol in a similar fashion tothat described in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (0.8 g, 87.75%). MS (ES): m/z 306.2[M+H]⁺

Synthesis of1-(6-aminopyridin-3-yl)-4-((dimethylamino)methyl)piperidin-4-ol(Intermediate AA56)

1-(6-aminopyridin-3-yl)-4-((dimethylamino)methyl)piperidin-4-ol(Intermediate AA56) was prepared from 5-fluoro-2-nitropyridine(Intermediate AA30-1) and 4-((dimethylamino)methyl)piperidin-4-ol in asimilar fashion to that described in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (0.85 g, 86.53%). MS (ES): m/z251.4 [M+H]⁺

Synthesis of 1-(6-aminopyridin-3-yl)-4-morpholinopiperidin-4-ol(Intermediate AA58)

1-(6-aminopyridin-3-yl)-4-morpholinopiperidin-4-ol (Intermediate AA58)was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and4-morpholinopiperidin-4-ol in a similar fashion to that described in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (0.40 g, 44.34%). MS (ES): m/z277.4 [M+H]⁺

Synthesis of 5-((oxetan-3-ylmethyl)sulfonyl)pyridin-2-amine(Intermediate AA59)

5-((oxetan-3-ylmethyl)sulfonyl)pyridin-2-amine (Intermediate AA59) wasprepared from 6-chloropyridine-3-sulfonyl chloride (Intermediate AA32-1)and 3-(bromomethyl)oxetane in a similar fashion to that described in5-((cyclobutylmethyl)sulfonyl)pyridin-2-amine (General processintermediate AA32). (0.19 g, 89.94%). MS (ES): m/z 277.4 [M+H]⁺

Synthesis of 5-(2-((dimethylamino)methyl)morpholino)pyridin-2-amine(Intermediate AA63)

5-(2-((dimethylamino)methyl)morpholino)pyridin-2-amine (IntermediateAA63) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1)and N,N-dimethyl-1-(morpholin-2-yl)methanamine in a similar fashion tothat described in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (0.60 g, 74.34%). MS (ES): m/z237.4 [M+H]⁺

Synthesis of1-(6-aminopyridin-3-yl)-3-((dimethylamino)methyl)piperidin-3-ol(Intermediate AA64)

1-(6-aminopyridin-3-yl)-3-((dimethylamino)methyl)piperidin-3-ol(Intermediate AA64) was prepared from 5-fluoro-2-nitropyridine(Intermediate AA30-1) and 3-((dimethylamino)methyl)piperidin-3-ol in asimilar fashion to that described in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (0.60 g, 78%). MS (ES): m/z 251.4[M+H]⁺

Synthesis of4-(6-aminopyridin-3-yl)-1-(2-(dimethylamino)ethyl)piperidin-2-one(Intermediate AA65)

Step-1 Synthesis of 4-bromo-1-(2-(dimethylamino)ethyl)pyridin-2(1H)-one(Intermediate AA65-1)

Prepared as described in WO2009/74812 A1.

Step-2, 3, 4 Synthesis of4-(6-aminopyridin-3-yl)-1-(2-(dimethylamino)ethyl)piperidin-2-one(Intermediate AA65)

4-(6-aminopyridin-3-yl)-1-(2-(dimethylamino)ethyl)piperidin-2-one(Intermediate AA65) was prepared from4-bromo-1-(2-(dimethylamino)ethyl)pyridin-2(1H)-one (IntermediateAA65-1) and2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in asimilar fashion to that described in4-(6-aminopyridin-3-yl)-1-methylpiperidin-2-one (Intermediate AA8) (1 g,65.65%). MS (ES): m/z 266.4 [M+H]⁺

Synthesis of1-(6-aminopyridin-3-yl)-4-(pyrrolidin-1-ylmethyl)piperidin-4-ol(Intermediate AA66)

1-(6-aminopyridin-3-yl)-4-(pyrrolidin-1-ylmethyl)piperidin-4-ol(Intermediate AA66) was prepared from 5-fluoro-2-nitropyridine(Intermediate AA30-1) 4-(pyrrolidin-1-ylmethyl)piperidin-4-ol in asimilar fashion to that described in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (1.5 gm, 90.90%) MS (ES): m/z 277.3[M+H]⁺

Synthesis of1-(6-aminopyridin-3-yl)-3-((4-methylpiperazin-1-yl)methyl)piperidin-3-ol(Intermediate AA67)

1-(6-aminopyridin-3-yl)-3-(4-methylpiperazin-1-yl)methyl)piperidin-3-ol(Intermediate AA67) was prepared from 5-fluoro-2-nitropyridine(Intermediate AA30-1) and3-((4-methylpiperazin-1-yl)methyl)piperidin-3-ol in a similar fashion tothat described in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (0.80 g, 79%). MS (ES): m/z 306.4[M+H]⁺

Synthesis of 1-(6-aminopyridin-3-yl)-3-(methoxymethyl)piperidin-3-ol(Intermediate AA69)

1-(6-aminopyridin-3-yl)-3-(methoxymethyl)piperi din-3-ol (IntermediateAA69) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1)and 3-(methoxymethyl)piperidin-3-ol in a similar fashion to thatdescribed in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (0.9 g, 84%). MS (ES): m/z 238.4[M+H]⁺

Synthesis of 4-(6-aminopyridin-3-yl)-4-azaspiro[2.5]octan-6-ol(Intermediate AA70)

4-(6-aminopyridin-3-yl)-4-azaspiro[2.5]octan-6-ol (Intermediate AA70)was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and4-azaspiro[2.5]octan-6-ol in a similar fashion to that described in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (0.17 g, 94%). MS (ES): m/z 220.4[M+H]⁺

Synthesis of (3S,4S)-1-(6-aminopyridin-3-yl)-3-fluoropiperidin-4-ol(Intermediate AA72)

(3 S,4S)-1-(6-aminopyridin-3-yl)-3-fluoropiperidin-4-ol (IntermediateAA72) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1)and (3S,4S)-3-fluoropiperidin-4-ol in a similar fashion to thatdescribed in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (2.5 g, 52%). MS (ES): m/z 212.2[M+H]⁺

Synthesis of((1R,55)-3-(6-aminopyridin-3-yl)-3-azabicyclo[3.2.1]octan-8-ol(Intermediate AA73)

(1R,5S)-3-(6-aminopyridin-3-yl)-3-azabicyclo[3.2.1]octan-8-ol(Intermediate AA73) was prepared from 5-fluoro-2-nitropyridine(Intermediate AA30-1) (1R,5S)-3-azabicyclo[3.2.1]octan-8-ol in a similarfashion to that described in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (0.9 g, 93%). MS (ES): m/z 220.2[M+H]⁺

Synthesis of 4-(6-aminopyridin-2-yl)-1-methylpiperidin-4-ol(Intermediate AA74)

Step-1 Synthesis of 4-(6-bromopyridin-2-yl)-1-methylpiperidin-4-ol(Intermediate AA74-2)

To Intermediate AA74-1 (7.5 g 31.77 mmol) dissolved in THF (25 mL) wasadded at −78° C. a solution of n-butyllithium (19 mL, 1.59 mmol, 1.5 eq)in diethyl ether (35 mL). After stirring at −78° C. for 30 min,1-methylpiperidin-4-one (3.6 g 31.77 mmol) was added. After stirring for45 min at −78° C., the reaction mixture was diluted with sodiumbicarbonate solution (200 mL) and extracted with ethyl acetate (3×150mL). The combined organic extracts were washed with brine (200 mL),dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by trituration with diethyl ether to affordIntermediate AA74-2 (3 g, 34.91%) MS (ES) m/z 272.2 (M+H)⁺.

Step-2 Synthesis ofN-(6-(4-hydroxy-1-methylpiperidin-4-yl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA74-3)

To a solution of Intermediate AA74-2 (1.7 g, 6.29 mmol) in 1,4-dioxane(20 mL) were added cyclopropanecarboxamide (0.641 g, 7.54 mmol, 1.2 eq)and CS₂CO₃ (6.1 g, 18.87 mmol, 3.0 eq). After degassing under N2 streamfor 15 min, Xantphos (0.363 g, 0.62 mmol, 0.1 eq) and Pd₂(dba)₃ (0.567g, 0.62 mmol, 0.1 eq) were added. After stirring at 110° C. for 2 h, thereaction mixture was cooled to RT, diluted with water (90 mL), andextracted with ethyl acetate (3×50 mL). The combined organic extractswere washed with brine (100 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with 2.0% methanol in DCM to affordIntermediate AA74-3 (1.7 g, 98.48%), MS (ES): m/z=276.2 (M+H)⁺.

Step-3 Synthesis of 4-(6-aminopyridin-2-yl)-1-methylpiperidin-4-ol(Intermediate AA74)

To a solution of Intermediate AA74-3 (1.7 g, 6.18 mmol) inmethanol:water (30 mL:5 mL) was added sodium hydroxide (2.47 g, 61.8mmol, 10 eq). After stirring for 16 h at 80° C., the reaction mixturewas concentrated under reduced pressure. The residue was diluted withwater (30 mL) at 10° C. and acidified with 1N hydrochloric acidadjusting pH-6-6.5. The solution was extracted with DCM (3×30 mL). Thecombined organic layer was washed with brine solution, dried over sodiumsulfate, and concentrated under reduced pressure to obtain crudematerial which was used in next Step without purification. IntermediateAA74 (0.750 g, 58.61%) MS (ES): m/z=208.2 (M+H)⁺.

Synthesis of 1-(6-aminopyridin-3-yl)-3-(methoxymethyl)piperidin-4-ol(Intermediate AA77)

Step-1 Synthesis of3-(hydroxymethyl)-1-(6-nitropyridin-3-yl)piperidin-4-ol (IntermediateAA77-1)

3-(hydroxymethyl)-1-(6-nitropyridin-3-yl)piperidin-4-ol (IntermediateAA77-1) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1)and 3-(hydroxymethyl)piperidin-4-ol in a similar fashion to thatdescribed in(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(Intermediate AA30-2). (2.1 g, 59%). MS (ES): m/z 254.2 [M+H]⁺

Step-2 Synthesis of3-(methoxymethyl)-1-(6-nitropyridin-3-yl)piperidin-4-ol (IntermediateAA77-2)

To a solution of 3-(hydroxymethyl)-1-(6-nitropyridin-3-yl)piperidin-4-ol(Intermediate AA77-1) (1.0 g, 3.9 mmol) in THF (25 mL), and sodiumhydride (60%)(0.189 g, 7.9 mmol, 2 eq) was added MeI (0.2 mL, 4.6 mmol,1.2 eq) at 0° C. After stirring at RT for 10 min, the reaction mixturewas diluted with ice cool water (50 mL) and extracted into ethyl acetate(100 mL×3). The combined organic layers were washed with brine solution,dried over sodium sulfate, and concentrated under reduced pressure. Theresidue was purified using Column chromatography eluting with 50% ethylacetate in hexane to afford Intermediate AA77-2 (0.600 g, 55%) MS (ES):m/z 267.2 [M+H]⁺

Step-3 Synthesis of1-(6-aminopyridin-3-yl)-3-(methoxymethyl)piperidin-4-ol (IntermediateAA77)

1-(6-aminopyridin-3-yl)-3-(methoxymethyl)piperidin-4-ol (IntermediateAA77) was prepared from3-(methoxymethyl)-1-(6-nitropyridin-3-yl)piperidin-4-ol (IntermediateAA77-2) in a similar fashion to that described in(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(Intermediate AA30-2). (0.9 g, 92%). MS (ES): m/z 238.2 [M+H]⁺

Synthesis of tert-butyl 3-(6-chloropyridin-2-yl)azetidine-1-carboxylate(Intermediate AA78)

Step-1 Synthesis of tert-butyl3-(6-chloropyridin-2-yl)azetidine-1-carboxylate (Intermediate AA78)

To a solution of Zn dust (0.830 g 12.72 mmol, 1.2 eq) in dry THF (25 mL)was added 1,2-dibromoethane (0.298 g, 1.59 mmol, 0.15 eq) at RT under N2atmosphere. After stirring at 80° C. for 10 min, the reaction mixturewas cooled and trimethylsilyl chloride (0.16 g 1.48 mmol, 0.14 eq)dissolved in THF was added. After stirring for 45 min at RT, a solutionof tert-butyl 3-iodoazetidine-1-carboxylate (3.0 g 10.60 mmol) in THFwas added. After stirring for 2 h at RT, a solution oftris(dibenzylideneacetone)dipalladium(O) (0.096 g 0.106 mmol, 0.01 eq),tri(2-furyl)phosphine (0.123 g 0.53 mmol, 0.05 eq) and IntermediateAA78-1 (2.76 g 11.55 mmol, 1.09 eq) in THF were added. After stirring at60° C. for 16 h, the reaction mixture was diluted with water (500 mL)and extracted with ethyl acetate (3×150 mL). The combined organicextracts were washed with brine (300 mL), dried over Na₂SO₄, filtered,and concentrated under reduced. The residue was purified by columnchromatography eluting with 20% ethyl acetate in hexane to affordIntermediate AA78 (1.2 g, 42.14%) MS (ES) m/z 269.2 (M+H)⁺

Synthesis of 6-(1-methylpiperidin-3-yl)pyridin-2-amine (IntermediateAA80)

Step-1 Synthesis of tert-butyl6-nitro-5′,6′-dihydro-[2,3′-bipyridine]-1′(2′H)-carboxylate(Intermediate AA80-1)

A 100 mL seal tube was charged 2-chloro-6-nitropyridine (IntermediateAA51-1) (2 g, 12. 61 mmol, 1.0 eq),tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(4.67 g, 15.13 mmol,1.2 eq), K₂CO₃ (5.26 g, 37.8 mmol), 1,4-dioxane (32mL) and water (8 mL). The mixture was degassed and purged with argon for10 min. The reaction mixture was treated with PdCl₂(dppf)DCM (0.51g,0.635 mmol 0.05 eq), purged with argon for 5 min, and heated at 100°C. for 3 h. After cooling to RT, the reaction mixture was diluted ethylacetate (200 mL) and water (200 mL). The organic layer was collected andthe aqueous phase was extracted with ethyl acetate (200 mL×2), combinedorganic extracts were washed with brine (100 mL) and dried over sodiumsulfate, filtered and concentrated under reduced pressure to affordcrude material which was purified using Column chromatography elutingwith 50% ethyl acetate in hexane to afford Intermediate AA80-1) (2.4 g,62%) MS (ES): m/z 306.2 [M+H]⁺

Step-2 Synthesis of 6-nitro-1′,2′,5′,6′-tetrahydro-2,3′-bipyridine(Intermediate AA80-2)

To a solution oftert-butyl-6-nitro-5,6-dihydro-[2,3-bipyridine]-1′(2H)′-carboxylate(AA80-1) (2.4 g, 7.86 mmol) in DCM (40 mL) at 0° C. was addedtrifluoracetic acid (8 mL) dropwise at RT. After stirring for 1 h, thereaction mixture quenched with saturated sodium bicarbonate (200 mL)solution and extracted in DCM (100 mL×3). The combined organic extractswere washed with brine (100 mL) and dried over sodium sulfate, filteredand concentrated under reduced pressure to afford crude material whichwas purified using Column chromatography eluting with 50% ethyl acetatein hexane to afford Intermediate AA80-2) (1.6 g, 99%). MS (ES): m/z206.10 [M+H]⁺

Step-3 Synthesis of1′-methyl-6-nitro-1′,2′,5′,6′-tetrahydro-2,3′-bipyridine (IntermediateAA80-3)

A solution of 6-nitro-1′,2′,5′,6′-tetrahydro-2′,3′-bipyridine(Intermediate AA80-2) (1.6 g,7.84 mmol,1.0 eq), in DMF (20 mL) wereadded K₂CO₃ (3.24 g, 23.52 mmol 3.0 eq) and methyl iodide (3.3 g, 23.52mmol 3.0 eq) at RT. After stirring for 4 h, the reaction mixture wasdiluted ethyl acetate (200 mL) and water (200 mL). The organic layer wascollected, and the aqueous phase was extracted with ethyl acetate (200mL×2). The combined organic extracts were washed with brine (100 mL) anddried over sodium sulfate, filtered and concentrated under reducedpressure to afford crude material which was purified using Columnchromatography eluting with 40% ethyl acetate in Hexane to affordmaterial (Intermediate AA80-3) (1.4 g, 81%). MS (ES): m/z 220.19[M+H]+

Step-4 Synthesis of 6-(1-methylpiperidin-3-yl)pyridin-2-amine(Intermediate AA80)

6-(1-methylpiperidin-3-yl)pyridin-2-amine (Intermediate AA80) wasprepared from 1′-methyl-6-nitro-1′,2′,5′,6′-tetrahydro-2,3′-bipyridine(Intermediate AA80-3) in a similar fashion to that described in(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process Intermediate AA30-2). (1 g, 90%). MS (ES): m/z 192.2[M+H]⁺

Synthesis of 5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-amine(Intermediate AA81)

Step-1 Synthesis of5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-amine (IntermediateAA81)

5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-amine (IntermediateAA81) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1)and 8-oxa-3-azabicyclo[3.2.1]octane in a similar fashion to thatdescribed in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (0.9 g, 93%). MS (ES): m/z 206.2[M+H]⁺

Synthesis of 6-([1,3′-bipyrrolidin]-1′-yl)pyridin-2-amine (IntermediateAA83)

5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-amine (IntermediateAA83) was prepared from 2-chloro-6-nitropyridine (Intermediate AA51-1)and 1,3′-bipyrrolidine in a similar fashion to that described intert-butyl3-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(General process intermediate AA6). (0.6 g, 93%). MS (ES): m/z 233.2[M+H]⁺

Synthesis of 5-(4-methyl-4-morpholinopiperidin-1-yl)pyridin-2-amine(Intermediate AA84)

5-(4-methyl-4-morpholinopiperidin-1-yl)pyridin-2-amine (IntermediateAA84) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1)and 4-(4-methylpiperidin-4-yl)morpholine in a similar fashion to thatdescribed in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (0.7 g, 91%). MS (ES): m/z 277.3[M+H]⁺

Synthesis of (1-(6-aminopyridin-3-yl)-4-methylpiperidin-4-yl)methanol(Intermediate AA85)

(1-(6-aminopyridin-3-yl)-4-methylpiperidin-4-yl)methanol (IntermediateAA85) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1)and 4-(4-methylpiperidin-4-yl)morpholine in a similar fashion to thatdescribed in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (0.5 g, 92%). MS (ES): m/z 222.3[M+H]⁺

Synthesis of tert-butyl1-(6-aminopyridin-2-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate(Intermediate AA86)

tert-butyl1-(6-aminopyridin-2-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate(Intermediate AA86) was prepared from 2-chloro-6-nitropyridine(Intermediate AA51-1) and tert-butylhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate in a similar fashion tothat described in tert-butyl 3-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (General process intermediateAA6). (1.1 g, 89%). MS (ES): m/z 305.2 [M+H]⁺

Synthesis of 7-(6-aminopyridin-3-yl)-2,7-diazaspiro[4.5]decan-1-one(Intermediate AA86)

7-(6-nitropyridin-3-yl)-2,7-diazaspiro[4. 5]decan-1-one (IntermediateAA87-1) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1)and 2,7-diazaspiro[4.5]decan-1-one in a similar fashion to thatdescribed in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrolepyrrole (General process intermediate AA30). (1.0 g, 89%). MS (ES): m/z347.3 [M+H]⁺.

Synthesis of 1-(6-chloro-5-fluoropyridin-3-yl)piperidin-4-ol(Intermediate AA88)

Step-1 Synthesis of8-(6-chloro-5-fluoropyridin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane(Intermediate AA88-2)

A solution of Intermediate AA88-1 (1.0 g, 4.80 mmol),1,4-dioxa-8-azaspiro[4.5]decane (0.755 g, 5.28 mmol, 1.1 eq) and K₂CO₃(2.0 g, 14.4 mmol, 3.0 eq) in toluene (10 mL) was degassed under N2stream. After 15 min, Xantphos (0.552 g, 0.96 mmol, 0.2 eq) andPd₂(dba)₃ (0.439 g, 0.48 mmol, 0.1 eq) were added. After stirring at110° C. for 2 h, the reaction mixture was cooled to RT, diluted withwater (80 mL), and extracted with ethyl acetate (3×50 mL). The combinedorganic extracts were washed with brine (80 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography eluting with 15% ethyl acetate inhexane to afford Intermediate AA88-2 (0.7 g, 54.01%) MS (ES): m/z=273.2(M+H)⁺

Step-2 Synthesis of 1-(6-chloro-5-fluoropyridin-3-yl)piperidin-4-one(Intermediate AA88-3)

A solution of Intermediate AA88-2 (0.7 g, 2.57 mmol) in 50% HCl (35 mL)was stirred at RT for 30 min. After completion of reaction, the reactionmixture was quenched with water (70 mL) and extracted with ethyl acetate(3×40 mL). The combined organic extracts were washed with brine (50 mL),dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was used in next Step without purification. IntermediateAA88-3 (0.6 g, 95.41%). MS (ES): m/z=229.05 (M+H)⁺

Step-3 Synthesis of 1-(6-chloro-5-fluoropyridin-3-yl)piperidin-4-ol(Intermediate AA88)

To a solution of Intermediate AA88-3 (0.6 g, 2.63 mmol) in THF (15 mL)was added portion wise sodium borohydride (0.150 g, 3.94 mmol, 1.5 eq)at RT. After stirring at RT and for 30 min, the reaction mixture wasquenched in water (40 mL) and extracted with ethyl acetate (3×20 mL).The combined organic extracts were washed with brine (50 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography eluting with 40% ethyl acetatein hexane to afford Intermediate AA88 (0.5 g, 82.61%) MS (ES): m/z=231.2(M+H)⁺

Synthesis of 5-(4-(morpholinomethyl)piperidin-1-yl)pyridin-2-amine(Intermediate AA89)

5-(4-(morpholinomethyl)piperidin-1-yl)pyridin-2-amine (IntermediateAA89) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1)and 4-(piperidin-4-ylmethyl)morpholine in a similar fashion to thatdescribed in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (0.5 g, 92%). MS (ES): m/z 277.3[M+H]⁺

Synthesis of tert-butyl4-(6-bromopyridin-2-yl)-4-methylpiperidine-1-carboxylate (IntermediateAA90)

1-(tert-butyl) 4-methyl4-(6-bromopyridin-2-yl)piperidine-1,4-dicarboxylate (IntermediateAA90-1) Synthesized as described in CA 2988721 A1

Step-1 Synthesis of tert-butyl4-(6-bromopyridin-2-yl)-4-(hydroxymethyl)piperidine-1-carboxylate(Intermediate AA90-2)

To a solution of Intermediate AA90-1 (1.2 g, 3.00 mmol) in THF (15 mL)was added dropwise lithium aluminum hydride (2M in THF) (4.5 mL, 9.0mmol, 3.0 eq) at 0° C. After stirring at 70° C. for 1 h, the reactionmixture was quenched in water (120 mL) and extracted with ethyl acetate(3×70 mL). The combined organic extracts were washed with brine (100mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica gel chromatography using10% ethyl acetate in hexane to afford Intermediate AA90-2 (1.0 g,89.62%) MS (ES): m/z=371.2 (M+H)⁺.

Step-2 Synthesis of tert-butyl4-(6-bromopyridin-2-yl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate(Intermediate AA90-3)

To a solution of Intermediate AA90-2 (1.0 g, 2.70 mmol) in DCM (10 mL)was added trimethylamine (0.5 mL, 4.05 mmol, 1.5 eq) and DMAP (10 mg).At 0° C. Methanesulfonyl chloride (0.22 mL, 2.97 mmol, 1.1 eq) was addeddropwise into the reaction mixture and stirred it at RT for 2 h. Aftercompletion of reaction, the reaction mixture was quenched in water (90mL) and extracted with ethyl acetate (2×70 mL). The combined organicextracts were washed with brine (50 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was used in nextStep without purification. Intermediate AA90-6 (1.0 g, 82.62%) MS (ES):m/z=450.2 (M+H)⁺.

Step-3 Synthesis of tert-butyl4-(6-bromopyridin-2-yl)-4-methylpiperidine-1-carboxylate (IntermediateAA90)

To a solution of Intermediate AA90-3 (1.0 g, 2.22 mmol) in DMF (30 mL)were add sodium iodide (0.661 g, 4.44 mmol, 2.0 eq) and zinc powder(0.725 g, 11.1 mmol, 5.0 eq). After stirring at 110° C. for 40 h, thereaction mixture was filtered. The filtrate was diluted with water (100mL) and extracted with ethyl acetate (100 mL×3). The combined organicsolution was dried, filtered, and concentrated. The residue was purifiedby silica gel chromatography using 10% ethyl acetate in DCM to affordIntermediate AA90 (0.2 g, 25.30%) MS (ES): m/z=355.2 (M+H)⁺.

Synthesis of 2-(1-(4-aminophenyl)piperidin-3-yl)propan-2-ol(Intermediate AA91)

2-(1-(4-aminophenyl)piperidin-3-yl)propan-2-ol (Intermediate AA91) wasprepared from 1-fluoro-4-nitrobenzene (Intermediate AA91-1) and2-(piperidin-3-yl)propan-2-ol in a similar fashion to that described in5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole(General process intermediate AA30). (0.6 g, 92%). MS (ES): m/z 2235.3[M+H]⁺

Synthesis of 2-chloro-6-(1-methylazetidin-3-yl)pyridine (IntermediateAA92)

Step-1 Synthesis of tert-butyl3-(6-chloropyridin-2-yl)azetidine-1-carboxylate (Intermediate AA92-1)

To a solution of Zn dust (407 mg, 6.2 mmol, 1.2 eq) in THF (10 mL) wasadded 1,2-dibromoethane (146 mg, 0.78 mmol, 0.15 eq) under N2atmosphere. After stirring at 80° C. for 10 min, the reaction was coolat RT and TMS-Cl (79 mg, 0.72, 0.14 eq) and tert-butyl3-iodoazetidine-1-carboxylate (1.38 g, 5.7 mmol, 1 eq) in THF (5 mL)were added. After stirring at RT for 2 h, Intermediate-AA78-1 (1.5 g,5.2 mmol, 1 eq), Pd₂(dba)₃ (47 mg, 0.052 mmol, 0.01 eq) andtri(2-furyl)phosphine (60 mg, 0.26 mmol, 0.05 eq) were added. Afterstirring at 55° C. for 16 h, the reaction mixture was quenched withwater (50 mL) and extracted with ethyl acetate (2×20 mL). The combinedorganic extracts were washed with brine (50 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure to afford crudeproduct which was purified by silica gel chromatography eluting with 10%ethyl acetate in hexane to afford Intermediate AA92-1 (390 mg, 29.62%)MS (ES): m/z=269.26 (M+H)⁺.

Step-2 Synthesis of 2-(azetidin-3-yl)-6-chloropyridine (IntermediateAA92-2)

2-(azetidin-3-yl)-6-chloropyridine (Intermediate AA92-2) was preparedfrom tert-butyl 3-(6-chloropyridin-2-yl)azetidine-1-carboxylate(Intermediate AA92-1) in a similar fashion to that described in step-2of Intermediate AA80-2 (155 g, 88%). MS (ES): m/z 169.7 [M+H]⁺

Step-3 Synthesis of 2-chloro-6-(1-methylazetidin-3-yl)pyridine(Intermediate AA92)

2-chloro-6-(1-methylazetidin-3-yl)pyridine (Intermediate AA92) wasprepared from 2-(azetidin-3-yl)-6-chloropyridine (Intermediate AA92-1)in a similar fashion to that described in step-3 of Intermediate AA80-3(120 mg, 78%). MS (ES): m/z 184.5 [M+H]⁺.

Synthesis of5-(2-(2-(dimethylamino)propan-2-yl)morpholino)pyridin-2-amine(Intermediate-AA93)

Step-1 Synthesis of 2-(4-benzylmorpholin-2-yl)propan-2-amine(Intermediate-AA93-2)

A solution of Ce(VI)C1 (36.6 g, 148.51 mmol, 2.0 eq) in dry THF (150 mL)was stirred at 45° C. for 2 h. The reaction mixture was cooled to RT andIntermediate-AA93-1 (15.0, 74.25 mmol) was added. The reaction mixturethen cooled to −10° C. and methyl lithium (3M) (61.0 mL, 185.62 mmol,2.5 eq) was added. After stirring for 30 min, the reaction mixture wasfiltered through celite-bed, diluted with water (100 mL), and extractedwith DCM (3×70 mL). The combined organic extracts were washed with brine(60 mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure to obtain crude material which was used in the next stepwithout further purification. (Intermediate-AA93-2) (10.0 g, 57.54%) asa brown solid. MS (ES): m/z=235.18 [M+H]⁺

Step-2 Synthesis of2-(4-benzylmorpholin-2-yl)-N,N-dimethylpropan-2-amine(Intermediate-AA93-3)

To a solution of Intermediate-AA93-2 (10.0 g, 42.73 mmol) andformaldehyde (2.56 g, 85.46 mmol, 2.0 eq) in dichloroethane (100 mL) wasadded trimethylamine (12 mL, 85.46 mmol, 2.0 eq). After stirring at RTfor 1 h. sodium triacetoxyborohydride (18.1 g, 85.46 mmol, 2.0 eq) wasadded in portion. After stirring for 16 h at RT, reaction mixture wasdiluted with water (200 mL) and sodium bicarbonate-solution (100 mL) andextracted with DCM (3×80 mL). The combined organic extracts were washedwith brine (150 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with 3.2% methanol gradient in DCM to afford Intermediate-AA93-3(4.0 g, 35.72%) as a brown solid. MS (ES): m/z=263.2 [M+H]⁺

Step-3 Synthesis of N,N-dimethyl-2-(morpholin-2-yl)propan-2-amine(Intermediate-AA93-4)

To a suspension of 20% palladium hydroxide on carbon (2.0 g) in methanol(20 mL), was added Intermediate-AA93-3 (4.0 g, 15.26 mmol). Afterhydrogenating at atmospheric pressure at RT for 16 h, the reactionmixture was filtered through celite-bed and washed with methanol. Thefiltrate was concentrated under reduced pressure to obtainIntermediate-AA93-4 (1.8 g, quantitative). MS (ES): m/z 173.16 [M+H]⁺

Step-4 Synthesis of N, N-dimethyl-2-(4-(6-nitropyridin-3-yl)morpholin-2-yl) propan-2-amine (Intermediate-AA93-5)

To a solution of Intermediate-AA93-4 (1.8 g, 10.46 mmol) andIntermediate-AA30-1 (0.890 g, 6.27 mmol, 0.6 eq) in DMSO (20 mL) wasadded dropwise N-ethyl-N-isopropylpropan-2-amine (7.1 mL, 41.84 mmol,3.0 eq). After stirring at 120° C. for 2 h, reaction mixture was dilutedwith water (100 mL) and extracted with ethyl acetate (3×80 mL). Thecombined organic extracts were washed with brine (100 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography eluting with 2.3% methanolgradient in DCM to afford Intermediate-AA93-5 (1.4 g, 45.52%). MS (ES):m/z=295.17 [M+H]⁺

Step-5 Synthesis of N,N-dimethyl-2-(morpholin-2-yl)propan-2-amine(Intermediate-AA93)

To a suspension of 10% palladium on carbon (0.7 g) in methanol (15 mL)was added Intermediate-AA93-5 (1.4 g, 4.76 mmol). After hydrogenating atatmospheric pressure at RT for 4 h, reaction mixture was filteredthrough Celite-bed and washed with methanol. The filtrate wasconcentrated under reduced pressure to obtain crude which was used inthe next step without further purification (Intermediate-AA93) (1.2 g,quantitative). MS (ES): m/z 265.2 [M+H]⁺

Synthesis of 3-((dimethylamino)methyl)-1-(6-nitropyridin-3-yl)piperidin-3-ol (Intermediate-AA94)

Step-1 Synthesis of tert-butyl 1-oxa-5-azaspiro[2.5]octane-5-carboxylate(AA95-2)

To a solution of Intermediate-AA94-1 (1 g, 10.3 mmol, 1 eq) in toluene(25 mL) were added hexane-2,5-dione (1.17 g, 10.3 mmol, 1 eq) and aceticacid (0.7 mL, 3.0 mmol, 0.3 eq). After stirring at 125° C. for 12 h, thereaction mixture was diluted with water (30 mL) and extracted with ethylacetate (2×90 mL). The combined organic layer was washed with brine (30mL), concentrated under reduced pressure to afford Intermediate-AA94-2(1 g). MS (ES): m/z 175.11 [M+H]⁺

Step-2 Synthesis of tert-butyl3-((dimethylamino)methyl)-3-hydroxypiperidine-1-carboxylate(Intermediate-AA94-3)

To a solution of Intermediate-AA94-2 (5 g, 28.5 mmol, 1 eq) in THF (50mL) at −78° C. was added n-BuLi (34 mL, 85.7 mmol, 3 eq). After stirringfor 30 min. tetrahydro-4H-pyran-4-one (5.71 g, 57.1 mmol, 1 eq) wasadded. After stirring at −78° C. for 20 min and then at 1 hr at RT, thereaction mixture was diluted with water (35 mL) and extracted with ethylacetate (2×50 mL). The combined organic solution was concentrated underreduced pressure to afford Intermediate-AA94-3 (420 mg, 44%). MS (ES):m/z 275.16 [M+H]⁺.

Step-3 Synthesis of4-(3-amino-1-methyl-1H-pyrazol-5-yl)tetrahydro-2H-pyran-4-ol(Intermediate AA94)

To a stirred solution of Intermediate-AA94-3 (2 g, 7.2 mmol, 1 eq) inethanol (30 mL) and water (15 mL) were added NH₂OH HCl (2.4 g, 33.4mmol, 4.6 eq) and KOH (1.2 g, 21.2, 3 eq). After stirring at RT for 2 h,the reaction mixture was concentrated under reduced pressure to affordIntermediate-AA94 (2 g, quantitative). MS (ES): m/z 197.12 [M+H]⁺

Synthesis of3-((dimethylamino)methyl)-1-(6-nitropyridin-3-yl)piperidin-3-ol(Intermediate-AA95)

Step-1 tert-butyl 1-oxa-5-azaspiro[2.5]octane-5-carboxylate(Intermediate-AA95-2)

To a suspension of potassium tert butoxide (7.2 g, 65.4 mmol, 1 eq) inDMSO (70 mL), was added trimethyl sulphonium iodide (14.4 g, 65.4 mmol,1 eq) dropwise. After stirring for 1.5 h, Intermediate-AA95-1 (9.1 g,45.8 mmol, 1 eq) and DME (15 mL) was added at RT. After stirring for 1h, the reaction mixture was diluted with water (30 mL) and extractedwith ethyl acetate (2×90 mL). The combined organic layer was washed withbrine (30 mL) and concentrated under reduced pressure to affordIntermediate-AA95-2 (7.4 g, 75%). MS (ES): m/z 213.14 [M+H]⁺

Step-2 Synthesis of tert-butyl3-((dimethylamino)methyl)-3-hydroxypiperidine-1-carboxylate(Intermediate-AA95-3)

To a suspension of Intermediate-AA95-2 (7.5 g, 35.2 mmol, 1 eq) wasadded dimethyl amine (75 mL, 10V). After stirring at RT for 2 h, thereaction was diluted with water (120 mL) and extracted with ethylacetate (2×100 mL). The combined organic solution was concentrated underreduced pressure to afford Intermediate-AA95-3 (7 g, 77%). MS (ES): m/z258.19 [M+H]⁺.

Step-3 Synthesis of 3-((dimethylamino)methyl)piperidin-3-ol(Intermediate AA95-4)

To a stirred solution of Intermediate-AA95-4 (5 g, 19.3 mmol, 1 eq) inDCM (50 mL), was added, TFA (12 mL). After stirring at RT for 2 h, thereaction mixture was concentrated under reduced pressure to affordIntermediate-AA95-4 (2.9 g). MS (ES): m/z 158.25 [M+H]⁺

Step-4 Synthesis of3-((dimethylamino)methyl)-1-(6-nitropyridin-3-yl)piperidin-3-ol(Intermediate-AA95-5)

To a stirred solution of Intermediate-AA95-4 (2.8 g, 17.7 mmol, 1 eq) inDMSO (21 mL) were added DIPEA (21.1 mL, 123 mmol, 7 eq) and5-fluoro-2-nitropyridine (2 g, 14.1 mmol, 1.5 eq). After stirring at120° C. for 4 h, the reaction mixture was diluted with water (100 mL)and extracted with ethyl acetate (3×70 mL). The combined organic layerwash with brine (100 mL), concentrated under reduced pressure. Theresidue was purified by column chromatography to affordIntermediate-AA95-5 (1.5 g, 40%). MS (ES): m/z 159.31 [M+H]⁺

Step-5 Synthesis of5-(2-(2-methoxypropan-2-yl)morpholino)pyridin-2-amine(Intermediate-AA95)

To a suspension of 10% Pd/C (1.0 g) in methanol was addedIntermediate-AA95-5 (2 g). After hydrogenating at atmospheric pressurefor 2 h, the reaction was filtered through celite bed and washed withmethanol. The filtrate was concentrated under reduced pressure to affordIntermediate-AA95 (1.6 g, 89.58%). MS (ES): m/z 250.35 [M+H]⁺.

Synthesis of 1-(6-aminopyridin-3-yl)-4-cyclopropylpiperidin-4-ol(Intermediate-AA96)

Step-1 Synthesis of 4-cyclopropyl-1-(6-nitropyridin-3-yl)piperidin-4-ol(Intermediate-AA96-2)

To a stirred solution of Intermediate-AA96-1 (500 mg, 3.5 mmol, 1 eq) inDMF (7 mL), were added K₂CO₃ (1.46 g, 10.5 mmol, 3 eq),Intermediate-AA30-1 (500 mg, 3.5 mmol, 1 eq) and TBAI (260 mg, 0.7 mmol,0.2 eq). After stirring at 110° C. for 2 h, the reaction mixture wasdiluted with water (30 mL) and extracted with ethyl acetate (2×40 mL).The combined organic layers were wash with brine (30 mL) andconcentrated under reduced pressure. The residue was purified by columnchromatography to afford Intermediate-AA96-2 (0.600 g, 64.36%). MS (ES):m/z 263.30 [M+1-1]⁺

Step-2 Synthesis of 1-(6-aminopyridin-3-yl)-4-cyclopropylpiperidin-4-ol(Intermediate-AA96)

To a suspension of 10% Pd/C (0.440 g) in methanol (10 mL) was addedIntermediate-AA96-) (0.9 g, 9.4 mmol, 1 eq). After hydrogenating atatmospheric pressure for 2 hr, the reaction was filtered through celitebed and washed with methanol. The filtrate was concentrated underreduced pressure to afford Intermediate-AA96 (600 mg, 75.23%). MS (ES):m/z 233.32 [M+H]⁺

Synthesis of 5-(2-(2-methoxypropan-2-yl)morpholino)pyridin-2-amine(Intermediate-AA97)

Step-1 Synthesis of tert-butyl2-(2-methoxypropan-2-yl)morpholine-4-carboxylate Intermediate(Intermediate-AA97-2)

To a stirred solution of Intermediate-AA178-2 (1 g, 4.08 mmol, 1 eq) inDMF (10 mL) at 0° C. was added sodium hydride (423 mg, 4.2 mmol, 1.2eq). After stirring for 15 min. CH₃I (1.76 g, 12.24 mmol, 3 eq) wasadded. After stirring for 2 h. at RT, the reaction was diluted withwater (100 mL) and extracted with ethyl acetate (3×70 mL). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with at 2 to 3% methanol in DCM to afford Intermediate-AA97-2(0.600 mg, 56.75%). MS (ES): m/z 259.12 [M+H]⁺

Step-2 Synthesis of 2-(2-methoxypropan-2-yl) morpholine (IntermediateAA97-3)

To a stirred solution of Intermediate-AA97-2 (3 g, 11.53 mmol, 1 eq) inDCM (30 mL) was added TFA (4 mL). After stirring at RT for 2 h, thereaction mixture was concentrated under reduced pressure to affordIntermediate-AA57-3 (2.5 g). MS (ES): m/z 159.31 [M+H]⁺

Step-3 Synthesis of2-(2-methoxypropan-2-yl)-4-(6-nitropyridin-3-yl)morpholine(Intermediate-AA97-4)

To a stirred solution of Intermediate-AA97-3 (2.1 g, 13.18 mmol, 1 eq)in DMSO (21 mL) were added DIPEA (20.2 mL, 118.2 mmol, 8 eq) and5-fluoro-2-nitropyridine (3.5 g, 19.78 mmol, 1.5 eq). After stirring at120° C. for 3, the reaction mixture was diluted with water (100 mL) andextracted with ethyl acetate (3×70 mL). The combined organic layers werewash with brine (100 mL) and concentrated under reduced pressure. Theresidue was purified by column chromatography to affordIntermediate-AA97-4 (1.5 g, 40%). MS (ES): m/z 159.31 [M+H]⁺

Step-4 Synthesis of5-(2-(2-methoxypropan-2-yl)morpholino)pyridin-2-amine(Intermediate-AA97)

To a suspension of 10% Pd/C (0.8 g) in methanol was addedIntermediate-AA97-4 (0.8 g). After hydrogenating at atmospheric pressurefor 2 h, the reaction mixture was filtered through celite bed and washedwith methanol. The filtrate was concentrated under reduced pressure toafford Intermediate-AA97 (1.5 g, 40%). MS (ES): m/z 159.31 [M+H]⁺

Synthesis of (1-(6-aminopyridin-3-yl)-5-methoxypiperidin-2-yl)methanol(Intermediate-AA98)

Step-1 Synthesis of (5-methoxypiperidin-2-yl)methanol(Intermediate-AA98-2)

To a solution of Intermediate-AA98-1 (1.5 g, 1.79 mmol, 1 eq) in MeOH(15 mL) was added Rh/Al2O3 (2 g, 1.29 mmol, 0.12 eq). Afterhydrogenating at 50 psi at RT for 24 h, the reaction mixture was filterthrough Celite-bed and washed with 10% methanol in DCM. The filtrate wasconcentrated under reduced pressure to obtain crude product which wasuse in the next step without further purification (Intermediate-AA98-2).(1 g, 63%). MS (ES): m/z=145.6 [M+H]⁺

Step-2 Synthesis of(5-methoxy-1-(6-nitropyridin-3-yl)piperidin-2-yl)methanol(Intermediate-AA98-3)

To a solution of Intermediate-AA98-2 (1 g, 7.04 mmol, 1 eq) in DMSO (10mL) were added DIPEA (4.54 g, 35.21 mmol, 5 eq) and5-fluoro-2-nitropyridine (1.22 g, 8.45 mmol, 1.2 eq). After stirring at110° C. for 4 h, the reaction mixture was diluted with water (30 mL) andextracted with DCM (3×30 mL). The combined organic extracts were washwith brine (30 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatography toafford Intermediate-AA98-3. (1.5 g, 81.49%) MS (ES): m/z=268.1 [M+H]⁺

Step-3 Synthesis of(1-(6-aminopyridin-3-yl)-5-methoxypiperidin-2-yl)methanol(Intermediate-AA98)

To a suspension of 10% palladium on carbon (0.800 g) in methanol (20 mL)was added Intermediate-AA98-3 (1.4 g). After hydrogenating atatmospheric pressure for 3 h, the reaction mixture was filter throughCelite-bed and washed with methanol. The filtrate was concentrated underreduced pressure to obtain product which was used in the next stepwithout further purification (Intermediate-AA98). (0.900 g, 72.6%). MS(ES): m/z=237 [M+H]⁺

Synthesis of 3-(6-chloropyridin-3-yl)THF-3-ol (Intermediate-AA99)

Step-1 Synthesis of 3-(6-chloropyridin-3-yl)THF-3-ol (Intermediate-AA99)

To a solution of Intermediate-AA99-1 (10 g, 52.63 mmol, 1 eq) in THF(100 mL) at −78° C. was added n-BuLi (1.6M) (65 mL, 105.2 mmol, 2 eq).After stirring for 1 h, Intermediate AA99-2 (6.78 g, 105.26 mmol, 2 eq)was added. After stirring at RT for 2 h, the reaction was diluted water(100 mL) and extract with ethyl acetate (2×200 mL). The combined organicextracts were washed with brine (250 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography (0-15% gradient elution EtOAc in hexane) to affordIntermediate-AA99 (7 g, 67.40%). MS (ES): m/z=304 [M+1]+.

Synthesis of tert-butyl4-(6-bromopyridin-2-yl)-4-methylpiperidine-1-carboxylate(Intermediate-AA100)

Step-1 Synthesis of tert-butyl4-(6-bromopyridin-2-yl)-4-cyanopiperidine-1-carboxylate (AA100-2)

To a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (5.38 g,25.05 mmol, 2 eq) in toluene (30 mL) was added LiHMDS (3.07 g, 19.02mmol, 1.5 eq) at 0° C. Intermediate-AA74-1 (3 g, 12.8 mmol, 1 eq) andPd₂(dba)₃ (0.117 g, 0.12 mmol, 0.1 eq) were then added. After stirringat RT for 16 h, the reaction mixture was quench with aq NaHCO₃ solution(50 mL) and extracted with ethyl acetate (3×80 mL). The combined organicextracts were washed with brine (60 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 0-50% ethyl acetate in hexane toafford Intermediate-AA100-2. (4.2 g, 90%) MS (ES): m/z=366 [M+H]⁺

Step-2 Synthesis of4-(6-bromopyridin-2-yl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylicacid (Intermediate-AA100-3)

To a solution of Intermediate-AA100-2 (4 g, 10.95, 1 eq), in EtOH (40mL) at 0° C. was added NaOH (2.191 g, 54.79 mmol, 5 eq). After stirringat 80° C. for 16 h, the reaction mixture with water (50 mL) andextracted with ethyl acetate (3×50 mL). The combined organic extractswere washed with brine (60 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 0-50% ethyl acetate in hexane to affordIntermediate-AA100-2. (2.5 g, 69.42%) MS (ES): m/z=385.3 [M+H]⁺

Step-3 Synthesis of 1-(tert-butyl) 4-methyl4-(6-bromopyridin-2-yl)piperidine-1,4-dicarboxylate(Intermediate-AA100-4)

To a solution of Intermediate-AA100-3 (2 g, 10.95, 1 eq) in DMF (20 mL)were added K₂CO₃ (1.43 g, 10.38 mmol, 2 eq) and MeI (0.878 g, 6.22 mmol,1.2 eq). After stirring for 30 min, the reaction mixture was dilutedwith water (30 mL) and extracted with ethyl acetate (3×40 mL). Thecombined organic extracts were wash with brine (50 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography by 10-40% ethyl acetate gradientin hexane to afford Intermediate-AA100-4. (1.8 g, 86.84%) MS (ES):m/z=399.3 [M+H]⁺

Step-4 Synthesis of tert-butyl 4-(6-bromopyridin-2-yl)-4-(hydroxymethyl)piperidine-1-carboxylate (Intermediate-AA100-5)

To a solution of Intermediate-AA100-4 (1.5 g, 3.759, 1 eq) in EtOH (20mL) at 0° C. was added NaBH4 (0.278 g, 7.51 mmol, 2 eq). After stirringat RT for 2 h, the reaction was concentrated under reduced pressure,diluted with water (50 mL), and extracted with ethyl acetate (3×40 mL).The combined organic extracts were washed with brine (50 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure to affordIntermediate-AA100-5. (1.1 g, 91%) MS (ES): m/z=371.28 [M+H]⁺

Step-5 Synthesis of tert-butyl4-(6-bromopyridin-2-yl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate(Intermediate-AA100-6)

To a solution of Intermediate-AA100-5 (1 g, 3.759, 1 eq) in DCM (10 mL)at 0° C. was added DIPEA (12.145 g, 9.41 mmol, 3.5 eq) andmethanesulfonyl chloride (0.460 g, 4.04 mmol, 1.5 eq) were added. Afterstirring at 0° C. for 30 min, the reaction mixture was diluted withwater (50 mL) and extracted with ethyl acetate (3×40 mL). The combinedorganic extracts were wash with brine (50 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure to affordIntermediate-AA100-6. (1.2 g, 99%) MS (ES): m/z=449.5 [M+H]⁺

Step-6 Synthesis of tert-butyl4-(6-bromopyridin-2-yl)-4-methylpiperidine-1-carboxylate(Intermediate-AA100)

To a solution of Intermediate AA100-6 (0.500 g, 1.1 mmol, 1 eq) in DMF(10 mL) were added NaI (0.829 g, 5.56 mmol, 2 eq) and Zn dust (0.144,2.22 mmol, 5 eq). After stirring at 100° C. for 24 h, the reactionmixture was filter through Celite-bed and washed with ethyl acetate. Thefiltrate was concentrated under reduced pressure. The residue waspurified by column chromatography eluting with 0-10% gradient elutionMeOH in DCM to afford Intermediate-AA100. (0.140 g, 35.41%) MS (ES):m/z=355 [M+H]⁺

Synthesis of (1-(6-aminopyridin-3-yl)-4-methoxypiperidin-4-yl)methanol(Intermediate-AA101)

Step-1 Synthesis of(4-methoxy-1-(6-nitropyridin-3-yl)piperidin-4-yl)methanol(Intermediate-AA101-2)

To a solution of Intermediate AA101-1 (3 g, 1.93 mmol, 1 eq) in DMSO (30mL) were added Intermediate-AA30-1 (2.7 g, 1.93 mmol, 1 eq) and DIPEA(16 mL, 9.6 mmol, 5 eq). After stirring at 110° C. for 3 h, the reactionmixture was diluted with water (30 mL) and extracted with DCM (3×30 mL).The combined organic extracts were wash with brine (30 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography eluting with 0-10% MeOH in DCM toafford Intermediate-AA101-2. (3.1 g, 54%), MS (ES): m/z=267.1 [M+H]⁺

Step-2 (1-(6-aminopyridin-3-yl)-4-methoxypiperidin-4-yl)methanol(Intermediate-AA101)

To a suspension of 10% palladium on carbon (1.5 g) in methanol (30 mL)was added Intermediate-AA54-5 (3 g). After hydrogenating at atmosphericpressure for 3 h, the reaction mixture was filter through Celite-bed andwashed with methanol. The filtrate was concentrated under reducedpressure to obtain crude product which was use in the next step withoutfurther purification (Intermediate-AA101). (2.2 g, 82%). MS (ES):m/z=237 [M+H]⁺

Synthesis of6-(2-(dimethylamino)ethyl)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine(Intermediate-AA102)

Step-1 Synthesis of5-(3,6-dihydro-2H-pyran-4-yl)-6-(2-(dimethylamino)ethyl)pyridin-2-amine(Intermediate AA102-1)

A solution of Intermediate AA156-5 (1.5, 6.14 mmol),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.5 g, 12.28 mmol, 2.0 eq), potassium phosphate tribasic (3.9 g, 18.42mmol, 3.0 eq) in 1,4-Dioxane:water (15 mL:4 mL) was degassed and purgedwith N2 for 15 min. X-Phos Pd G3 (0.519 g, 0.61 mmol, 0.1 eq) was thenadded. After stirring at 100° C. for 20 min, the reaction mixture wascooled to RT, diluted with water (80 mL), and extracted with ethylacetate (2×40 mL). The combined organic extracts were washed with brine(50 mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography eluting with3.7% methanol gradient in DCM to obtain Intermediate AA102-1 (2.0 g,98.70%), MS (ES): m/z 248.17 [M+H]⁺

Step-2 Synthesis of6-(2-(dimethylamino)ethyl)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine(Intermediate AA102)

To a solution of Intermediate AA102-1 (2.0 g, 8.09 mmol) in methanol (20mL) and THF (10 mL) were added ammonium format (2.0 g, 32.36 mmol, 4.0eq), acetic acid (1.4 mL, 0.7V) and 20% wet palladium hydroxide oncarbon (1 g). After stirring under an atmosphere of hydrogen gas for 24h at RT, the reaction mixture was filtered through Celite bed. Thefiltrate was concentrated under reduced pressure, diluted with sat.NaHCO₃ solution and extracted by DCM. The organic solution wasconcentrated to afford Intermediate AA102 (1.3 g, 64.47%). MS (ES): m/z250.1 [M+H]⁺

Synthesis of5-(3-(2-(dimethylamino)propan-2-yl)piperidin-1-yl)pyridin-2-amine(Intermediate-AA103)

Step-1 Synthesis of tert-butyl3-(2-aminopropan-2-yl)piperidine-1-carboxylate (Intermediate AA103-2)

To a solution of the CeCl₃(12.2 g, 47.6 mmol, 2.0 eq) in THF (50 mL)stirred at 45° C. for 2 h was added Intermediate AA103-1 (5 g, 23.8mmol) at RT. After cooling to −10° C., CH₃Li (20 mL, 60 mmol, 2.5 eq)was added dropwise. After stirring for 30 min at RT, the reactionmixture was diluted with DCM (300 mL) and water (500 mL). The organiclayer was collected, and the aqueous phase was extracted with DCM (2×300mL). The combined organic extracts were washed with brine (10 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure to obtainIntermediate AA103-2 (3.5 g, 60%) MS (ES): m/z=243.36[M+H]⁺

Step-2 Synthesis of tert-butyl3-(2-(dimethylamino)propan-2-yl)piperidine-1-carboxylate(Intermediate-AA103-3)

To a solution of Intermediate-AA103-2 (8.0 g, 32.8 mmol) andformaldehyde (1.5 g, 49.2 mmol, 1.5 eq) in methanol (100 mL) was addedacetic acid (0.4 g, 8.2 mmol, 0.25 eq). After stirring at RT for 1 h,sodium cyanoborohydride (2.0 g, 39.36 mmol, 1.2 eq) was added portionwise. After stirring for 45 min at RT, the reaction mixture wasconcentrated. The residue was diluted with water (100 mL) and theresulting solid collected by filtration. The solid was purified bycolumn chromatography eluting with 5.0% ethyl acetate gradient inhexanes to afford Intermediate-AA103-3) (2.6 g, 29.74%). MS (ES):m/z=271.1 [M+H]⁺

Step-3 Synthesis of N,N-dimethyl-2-(piperidin-3-yl)propan-2-amine(Intermediate-AA103-4)

To a solution of (Intermediate-AA103-3) (3 g) in DCM (30 mL), TFA (12mL) was added at 0° C. Reaction mixture was stirred at RT for 30 min.Reaction mixture was concentrate under reduced pressure to obtain crudeto give the title compound Intermediate-AA103-4 (1.5 g, 79.8%). MS (ES):m/z=171.3 (M+H).

Step-4 Synthesis ofN,N-dimethyl-2-(1-(6-nitropyridin-3-yl)piperidin-3-yl)propan-2-amine(AA103-5)

To a solution of (Intermediate-AA103-4) (1.4 g, 8.2 mmol, 1 eq) and5-fluoro-2-nitropyridine (0.8 g, 9.84 mmol, 1.2 eq), DIPEA (5.2 mL, 41mmol, 5 eq) in DMSO (15 mL) and the reaction was heated at 90° C. for 1h. Reaction mixture was cooled at RT and then diluted with water (50 mL)and ethyl acetate (100 mL). The organic layer was collected, and theaqueous phase was extract with ethyl acetate (300 mL). The combinedorganic extracts were washed with brine (200 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by column to afford the title compound (Intermediate-AA103-5)(1.5 g, 62.19%). MS (ES): m/z=293.38 [M+1]+

Step-5 Synthesis of5-(3-(2-(dimethylamino)propan-2-yl)piperidin-1-yl)pyridin-2-amine(Intermediate-AA103)

To a suspension of 10% Pd/c (500 mg) in MeOH (20 mL), was added(AA111-3) (1 g) and Reaction mixture was stirred at RT for 1 h withgiven H2 gas atmospheric pressure. The reaction mixture was filtratethrough celite bed and organic layer was evaporate in vacuum to obtaincrude (Intermediate-AA103) (600 mg, 66%), Used in the next step withoutpurification MS (ES): m/z=263.40 [M+H]⁺.

Synthesis of tert-butyl4-((6-chloropyridin-3-yl)methyl)-3,3-dimethylpiperazine-1-carboxylate(AA104)

Step-1 tert-butyl4-((6-chloropyridin-3-yl)methyl)-3,3-dimethylpiperazine-1-carboxylate(Intermediate-AA104)

A solution of Intermediate-AA104-1(1.0 gm, 6017 mmol,1.0 eq) inAcetonitrile (10 mL), were add Intermediate-AA104-2 (1.58 gm, 7.4mmol,1.2 eq) and K₂CO₃(2.55 gm, 18.5 mmol,3.0 eq). Reaction mixture washeated 80° C. for 2 h. After completion of reaction, the reactionmixture washed with water (50 mL) and extracted with DCM (3×30 mL). Thecombined organic extracts were washed with brine (60 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure to obtaincrude. The residue was used in the next step without furtherpurification. (Intermediate-AA104) (1.5 g, 71.50%), MS (ES):m/z=340.17[M+H]⁺

Synthesis of 6-methyl-5-(4-methylpiperazin-1-yl)pyridin-2-amine(Intermediate-AA105)

Step-1 Synthesis of tert-butyl (5-bromo-4-cyanopyridin-2-yl)carbamate(Intermediate-AA105-2)

A solution of (Intermediate-AA105-1) (4.0 g, 19.41 mmol) and1-methylpiperazine (1.7 g, 17.08 mmol, 0.88 eq), sodium tert-butoxide(3.7 g, 38.82 mmol, 2.0 eq) in toluene (40 mL) degassed under N2 stream.After 15 min Xantphos (2.2 g, 3.88 mmol, 0.2 eq) and Pd₂(dba)₃ (1.7 g,1.94 mmol, 0.1 eq) added and the reaction was stirred at 100° C. for 16h. The reaction mixture was cooled to RT and then diluted water (150 mL)and extracted with ethyl acetate (3×50 mL). The combined organicextracts were washed with brine (100 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 0-50% ethyl acetate in hexane toafford Intermediate-AA105-2 (2.0 g, 45.74%) as a brown solid. MS (ES):m/z=226.1 [M+H]⁺

Step-2 Synthesis ofN-(6-methyl-5-(4-methylpiperazin-1-yl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate-AA105-3)

A solution of Intermediate-AA105-2 (2.0 g, 8.88 mmol),1-cyclopropanecarboxamide (1.5 g, 17.76 mmol, 2.0 eq) and CS₂CO₃ (8.6 g,26.64 mmol, 3.0 eq) in 1,4-dioxane (20 mL) was degassed under N2 stream.After 15 min, Xantphos (0.5 g, 0.88 mmol, 0.1 eq) and Pd₂(dba)₃ (0.8 g,0.88 mmol, 0.1 eq) were added. After stirring at 120° C. for 16 h, thereaction mixture was cooled to RT, diluted water (80 mL) and extractedwith ethyl acetate (3×50 mL). The combined organic extracts were washedwith brine (80 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with 2.5-3.0% methanol gradient in DCM to affordIntermediate-AA105-3 (1.3 g, 53.47%) MS (ES): m/z=275.18 [M+H]⁺

Step-3 Synthesis of 6-methyl-5-(4-methylpiperazin-1-yl)pyridin-2-amine(Intermediate-AA105)

To a solution of Intermediate-AA105-3 (1.2 g, 4.37 mmol) in methanol (20mL) and water (5 mL) was added sodium hydroxide (1.7 g, 43.7 mmol, 10.0eq). After stirring at 70-80° for 16 h, the reaction mixtureconcentrated under reduced pressure. The residue was extracted with 10%methanol in DCM (3×70 mL). The combined organic extracts were washedwith brine (80 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was used in the next step without furtherpurification (Intermediate-AA105) (8.0 g, quantitative %), MS (ES): m/z207.16 [M+H]⁺

Synthesis of 1-(6-aminopyridin-3-yl)-3,6-dimethylpiperidin-3-ol(Intermediate-AA106)

Step-1 Synthesis of 3,6-dimethylpiperidin-3-ol (Intermediate-AA106-2)

To a solution of Intermediate-AA106-1 (2 g) in DCM (20 mL) was added TFA(6 mL) at 0° C. After stirring at RT for 30 min, the reaction mixturewas concentrated under reduced pressure to obtain the title compoundIntermediate-AA106-2 (1 g, 88.74%). MS (ES): m/z=130.2 (M+1)+

Step-2 Synthesis of 3,6-dimethyl-1-(6-nitropyridin-3-yl)piperidin-3-ol(AA106-3)

To a solution of Intermediate-AA106-2 (1.4 g, 10.7 mmol, 1 eq) in DMSO(15 mL) were added 5-fluoro-2-nitropyridine (1 g, 12.84 mmol, 1.2 eq)and DIPEA (6 mL, 53.5 mmol, 5 eq). After stirring at 90° C. for 1 h, thereaction mixture was cooled to RT and diluted with water (50 mL) andethyl acetate (100 mL). The organic layer was collected, and the aqueousphase was extract with ethyl acetate (300 mL). The combined organicextracts were washed with brine (200 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn to afford the title compound (Intermediate-AA106-2) (1.4 g, 55%).MS (ES): m/z=252.29 [M+1]+

Step-3 Synthesis of 1-(6-aminopyridin-3-yl)-3,6-dimethylpiperidin-3-ol(Intermediate-AA106)

To a suspension of 10% Pd/c (2.5 g) in MeOH (20 mL) was addedIntermediate AA156-3 (5 g). After stirring at RT for 1 h with H2 gas atatmospheric pressure, the reaction mixture was filtered through celitebed and filtrate was evaporated in vacuum to obtain Intermediate-AA106(4 g, 90.74%) which was used in the next step without purification MS(ES): m/z=221.30 [M+H]⁺.

Synthesis of 1-((6-chloropyridin-3-yl)methyl)-4-methylpiperazine(Intermediate-AA108)

Step-1 Synthesis of 1-((6-chloropyridin-3-yl)methyl)-4-methylpiperazine(Intermediate-AA108)

To a solution of Intermediate-AA104-1 (2 g, 12.5 mmol, 1 eq) in DMSO (20mL) were added 1-methylpiperazine (1.5 g, 15 mmol, 1.2 eq) and K₂CO₃(5.17 g, 37.5 mmol, 3 eq). After stirring at 90° C. for 4 h, thereaction mixture was cooled at RT, diluted with water (50 mL), andextracted with ethyl acetate (100 mL). The organic layer was collected,and the aqueous phase was extract with ethyl acetate (200 mL). Thecombined organic extracts were washed with brine (100 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column to afford the title compound (Intermediate-AA108)(1.4 g, 50.24%). MS (ES): m/z=226.72 [M+1]+.

Synthesis of5-(3-((dimethylamino)methyl)-3-methoxypiperidin-1-yl)pyridin-2-amine(Intermediate-AA109)

Step-1 Synthesis of1-(3-methoxy-1-(6-nitropyridin-3-yl)piperidin-3-yl)-N,N-dimethylmethanamine(Intermediate-AA109-1)

To a solution of Intermediate-AA102-5 (1 g, 3.5 mmol, 1 eq) in THF (10mL) was added NaH (0.257 g, 10.7 mmol, 3 eq) at 0° C. After stirring for30 min, CH₃I (0.294 g, 7 mmol, 2 eq) was added. After stirring at RT for1 h, the reaction mixture was diluted with water (50 mL) and extractedwith ethyl acetate (50 mL). The combined organic extracts were washedwith brine (60 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatography toafford Intermediate-AA109-1 (600 mg, 57%). MS (ES): m/z=294.17 [M+1]+

Step-2 Synthesis of5-(3-((dimethylamino)methyl)-3-methoxypiperidin-1-yl)pyridin-2-(Intermediate-AA109)

To a suspension of 10% palladium on charcoal (0.385 g) in methanol (10mL) was added Intermediate-AA109-1 (0.600 g, 2.04 mmol). Afterhydrogenating for 3 h at atmospheric pressure, the reaction mixture wasfiltered through celite-bed and washed with methanol. The filtrate wasconcentrated under reduced pressure to obtain Intermediate-AA109 whichwas used in the next step without further purification. (500 mg, 92%).MS (ES): m/z 264.37 [M+H]⁺.

Synthesis of 6-(1-methyl-1,6-diazaspiro[3.4]octan-6-yl)pyridin-2-amine(Intermediate-AA110)

Step-1 Synthesis of1-methyl-6-(6-nitropyridin-2-yl)-1,6-diazaspiro[3.4]octane(Intermediate-AA110-2)

To a solution of Intermediate-AA110-1 (0.100 g, 0.793 mmol), in dioxanewere added 1-methyl-1,6-diazaspiro[3.4]octane (0.150 g, 0.952 mmol, 1.2eq) and K₃PO₄ (0.336 g, 1.58 mmol, 2 eq). After degassing under N2stream for 20 min, Pd₂(dba)₃ (0.072 g, 0.079 mmol, 0.1 eq) and Xantphos(0.045 g, 0.079 mmol, 0.1 eq) were added After stirring at 100° C. for 1h, the reaction mixture was cooled at RT and filtered through celitebed. The filtrate was diluted with ethyl acetate (20 mL) and water (20mL). The organic layer was collected, and the aqueous phase wasextracted with ethyl acetate (2×20 mL). The combined organic extractswere wash with brine (20 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography (0-2% gradient elution MeOH in DCM) to affordIntermediate-AA110-2 (0.130 g, 83%). MS (ES): m/z=248.13 [M+H]⁺

Step-2 Synthesis of6-(1-methyl-1,6-diazaspiro[3.4]octan-6-yl)pyridin-2-amine(Intermediate-AA110)

To a suspension of palladium on charcoal (0.300 g) in methanol (5 mL),was added Intermediate-AA110-2 (0.300 g). After hydrogenating for 2 h,the reaction was filter through celite-bed and washed with methanol. Thefiltrate was concentrated under reduced pressure to obtainIntermediate-AA110 which was used in the next step without furtherpurification. (0.210 g, 79%). MS (ES): m/z=218.15 [M+H]⁺

Synthesis of 1-(4-(6-aminopyridin-3-yl)morpholin-2-yl)ethan-1-ol(Intermediate-AA111)

Step-1 Synthesis of 1-(4-(6-nitropyridin-3-yl)morpholin-2-yl)ethan-1-ol(Intermediate AA111-2)

To a solution of Intermediate-AA111-1 (1.4 g, 11.1 mmol, 2.0 eq) in DMSO(15 mL) were added Intermediate-AA30-1 (0.8 g, 5.5 mmol) and DIPEA (4.8mL, 27.7 mmol, 5 eq). After stirring at 90° C. for 1 h, the reactionmixture was cooled at RT and diluted with water (50 mL) and ethylacetate (100 mL). The organic layer was collected, and the aqueous phasewas extract with ethyl acetate (300 mL). The combined organic extractswere washed with brine (200 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography (1% gradient elution MeOH in DCM). The purified solid wastriturated with diethyl ether and the resulting solid was collected byfiltration to afford the title compound (Intermediate-AA111-2) (1.8 g,66.5%). MS (ES): m/z=253.2 [M+H]+

Step-2 Synthesis of 1-(4-(6-aminopyridin-3-yl)morpholin-2-yl)ethan-1-ol(Intermediate-AA111)

To a suspension of 10% Pd/c (1.8 g) in MeOH (20 mL) was addedIntermediate AA111-2 (1.8 g). After hydrogenating for 1 h, the reactionmixture was filtrate through celite bed and organic layer was evaporatein vacuum to obtain Intermediate-AA111 (1.7 g, quantitative) which wasused in the next step without purification MS (ES): m/z=223.2[M+H]⁺.

Synthesis of2-(4-(6-aminopyridin-3-yl)-1-methylpiperazin-2-yl)propan-2-ol(Intermediate-AA112)

Step-1 Synthesis of 1-(tert-butyl) 3-methyl4-methylpiperazine-1,3-dicarboxylate (Intermediate Intermediate-AA112-2)

To a solution of the Intermediate-AA112-1 (5 g, 20.4 mmol), in THF (80mL) was added DIPEA (3.2 g, 24.5 mmol, 1.2 eq). After stirring at RT for30 min, MeI (5.8 g, 41.0 mmol, 2 eq) was added. After stirring at 60° C.for 4 h, the reaction was quenched with water (100 mL) and extracted inethyl acetate (3×40 mL). The combined organic layer was washed withbrine, passed through a hydrophobic filter, and evaporated in vacuum.The residue was purified by column chromatography eluting with 25 to 50%ethyl acetate in hexane to give the title compound Intermediate-AA112-2(2.5 g, 47.2%). MS (ES): m/z 258.3[M+1]⁺

Step-2 Synthesis of tert-butyl3-(2-hydroxypropan-2-yl)-4-methylpiperazine-1-carboxylate(Intermediate-AA112-3)

To a solution of Intermediate-AA112-2 (9 g, 68 mmol) in chloroform (100mL), at −78° C. was added MeMgBr (13.3 g, 74 mmol, 1.1 eq). Afterstirring at −78° C. to 0° C. over 4 h, the reaction was quenched withHCl to ˜pH-7, diluted with water (100 mL) and extracted with ethylacetate (3×40 mL). The combined organic layers were washed with brine,passed through a hydrophobic filter, and evaporated in vacuum. Theresidue was purified by column chromatography eluting with 25 to 30%ethyl acetate in hexane to give the title compound Intermediate-AA112-3(1 g, 40%). MS (ES): m/z 258.3[M+1]⁺

Step-3 Synthesis of 2-(1-methylpiperazin-2-yl) propan-2-ol(Intermediate-AA112-4)

To a solution of Intermediate-AA112-3 (1 g, 3.9 mmol) in DCM (5 mL) at0° C. was added HCl in dioxane (10 mL). After stirring at RT for 2 h,the reaction was concentrated under reduced pressure to afford the titlecompound which was used in the next step without purification.Intermediate-AA112-4 (0.500 g, 81.63%). MS (ES): m/z 158.2[M+1]⁺

Step-4 Synthesis of 2-(1-methyl-4-(6-nitropyridin-3-yl)piperazin-2-yl)propan-2-ol (Intermediate-AA112-5)

To a solution of the Intermediate-AA112-4 (0.8 g, 5.6 mmol)5-fluoro-2-nitropyridine (Intermediate AA30-1) (1.0 g, 6.7 mmol, 1.2 eq)in DMSO (8 mL) were added TBAI (0.21 gm, 0.5 mmol, 0.1 eq) and K₂CO₃(1.5 g, 11.6 mmol, 0.2 eq). After stirring at 100° C. for 3 h, thereaction mixture was cooled at RT, diluted with water, and extractedwith ethyl acetate (20 mL). The organic layer was collected, and theaqueous phase was extracted with ethyl acetate (2×30 mL). The combinedorganic extracts were washed with brine (10 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography to give the title compoundIntermediate-AA112-5 (0.8 g, 56.4%). MS (ES): m/z 283.3[M+1]⁺

Step-5 Synthesis of 2-(4-(6-aminopyridin-3-yl)-1-methylpiperazin-2-yl)propan-2-ol (Intermediate-AA112)

To a suspension of 10% Pd/C (0.6 g) in methanol (25 mL) was addedIntermediate-AA112 (0.8 g). After hydrogenating at atmospheric pressurefor 2 h, the reaction mixture was filtrate through celite bed. Thefiltrate was evaporated in vacuum to obtain Intermediate-AA112 (0.8 g,quantitative) which used in the next step without purification. MS (ES):m/z 250[M+H]⁺.

Synthesis of 2-(4-(6-aminopyridin-3-yl)-1,4-oxazepan-6-yl)propan-2-ol(Intermediate-AA113)

Step-1 Synthesis of 4-(tert-butyl) 6-methyl1,4-oxazepane-4,6-dicarboxylate (Intermediate-AA113-3)

To a solution of Intermediate-AA113-1 (1 g, 6.2 mmol) in acetone wasadded K₂CO₃ (2.57 g, 18.6 mmol, 3.0 eq). After stirring at RT for 5 min,Intermediate-AA113-2 (1.6 mL, 6.2 mmol) was added dropwise. Afterstirring at reflux for 1 h, the reaction mixture was cooled at RT anddiluted with ethyl acetate (20 mL) and water (20 mL). The organic layerwas collected, and the aqueous phase was extracted with ethyl acetate(2×30 mL). The combined organic extracts were washed with brine (20 mL),dried over Na₂SO₄, filtered, and concentrated under reduced pressure toafford Intermediate-AA113-3 (0.7 g, 43.52%), MS (ES): m/z=259[M+1-1]⁺

Step-2 Synthesis tert-butyl6-(2-hydroxypropan-2-yl)-1,4-oxazepane-4-carboxylate(Intermediate-AA113-4)

To a solution of Intermediate-AA113-3 (0.5 g, 26.7 mmol), in THF (5 mL)at 0° C. was added MeMgCl (4 mL) dropwise. After stirring at RT for 30min, the reaction was quench with water (100 mL) and extracted in ethylacetate (3×40 mL). The combined organic layer was wash with brine,passed through a hydrophobic filter, and evaporated in vacuum to obtainIntermediate-AA113-4 (0.5 g, 79.88%) which was used in the next stepwithout purification. MS (ES): m/z=259[M+1]⁺

Step-3 Synthesis 2-(1,4-oxazepan-6-yl)propan-2-ol (Intermediate-AA113-5)

To a solution of Intermediate-AA113-4 (0.5 g) into DCM (5 mL) at 0° C.was added TFA (3.5 mL). After stirring at RT for 30 min, the reactionmixture was concentrated under reduced pressure to obtain to give thetitle compound Intermediate-AA113-5 (0.30 g, 97.73%). MS (ES): m/z=159(M+H).

Step-4 Synthesis of2-(4-(6-nitropyridin-3-yl)-1,4-oxazepan-6-yl)propan-2-ol (AA113-6)

To a solution of the Intermediate-AA113-5 (1.6 g, 5.6 mmol) in DMSO (40mL) with DIPEA (1.4 gm, 6.7 mmol, 1.2 eq) at RT was added dropwise5-fluoro-2-nitropyridine (1.6 g, 5.6 mmol). After stirring for 1 h at100° C., the reaction mixture was cooled at RT and diluted with ethylacetate (20 mL) and water (15 mL). The organic layer was collected, andthe aqueous phase was extracted with ethyl acetate (2×30 mL). Thecombined organic extracts were washed with brine (10 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography eluting with 0.5% methanolgradient in DCM to give title compound (Intermediate-AA113-6) (0.3 g,57%), MS (ES): m/z=281[M+H]⁺

Step-5 Synthesis of2-(4-(6-aminopyridin-3-yl)-1,4-oxazepan-6-yl)propan-2-ol(Intermediate-AA113)

To a suspension of 10% Pd/c (0.150 g) in MeOH (6 mL) was addedIntermediate-AA113-6 (0.3 g). After stirring at RT with H2 gasatmospheric pressure, the reaction mixture was filtered through a celitebed. The organic solution was evaporated in vacuum to affordIntermediate-AA113 (0.256 g, quantitative) which was used in the nextstep without purification. MS (ES): m/z=251[M+1]+

Synthesis of tert-butyl 1-(6-aminopyridin-2-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (Intermediate-AA114)

Step-1 Synthesis of tert-butyl1-(6-aminopyridin-2-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate(Intermediate-AA114-2)

To a solution of Intermediate-AA114-1 (1 g, 6.3 mmol, 1 eq) in dioxane(10 mL) were added tert-butylhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (1.6 g, 7.5 mmol, 1.2eq) and K₂CO₃ (1.7 g, 12.6 mmol, 2 eq). After degassing under N2 streamfor 20 min, Pd₂(dba)₃ (0.57 g, 0.63 mmol, 0.1 eq) and Xantphos (0.36 g,0.63 mmol, 0.1 eq) were added. After stirring at 100° C. for 1 h, thereaction mixture was cooled at RT and filtered through celite bed. Thefiltrate was diluted with ethyl acetate (50 mL) and water (50 mL). Theorganic layer was collected, and the aqueous phase was extract withethyl acetate (2×30 mL). The combined organic extracts were washed withbrine (20 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with 0-15% gradient elution EtOAc in hexane to affordIntermediate-AA114-2 (1.8 g, 93.85%). MS (ES): m/z=304 [M+1]+

Step-2 Synthesis of1-(6-nitropyridin-2-yl)octahydropyrrolo[3,4-b]pyrrole(Intermediate-AA114-3)

To a solution of Intermediate-AA114-2 (1.3 g, 3.88 mmol, 1 eq) in DCM,was added TFA (6.5 mL). After stirring at RT for 1 h, the reaction wasneutralized using saturated sodium bicarbonate solution. The solutionwas extracted with DCM (3×40 mL) and the combined organic layer wereconcentrated under reduced pressure to afford Intermediate-AA114-3(0.750 g, 94.85%). MS (ES): m/z=204 [M+1]+

Step-3 Synthesis of5-methyl-1-(6-nitropyridin-2-yl)octahydropyrrolo[3,4-b]pyrrole(Intermediate-AA114-4)

To a solution of Intermediate-AA114-3 (0.485 g, 2.07 mmol, 1 eq) in THFat 0° C. was added NaH (0.033 g, 4.14 mmol, 2 eq). After stirring at RTfor 15 min, MeI (0.440 g, 3.10 mmol, 1.5 eq) was added. After stirringfor 2 h, the reaction was diluted ethyl acetate (200 mL) and water (20mL). The organic layer was collected, and the aqueous phase wasextracted with ethyl acetate (2×30 mL). The combined organic extractswere washed with brine (20 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford Intermediate-AA114-4(0.510 g, 86.52%). MS (ES): m/z=248 [M+1]+.

Step-4 Synthesis of6-(5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)pyridin-2-amine(Intermediate-AA114)

To a suspension of 10% palladium on charcoal (0.385 g) in methanol (10mL) was added Intermediate-AA114-4 (0.770 g, 3.101 mmol). After stirringunder hydrogen gas at atmospheric pressure for 3 h at RT, the reactionmixture was filtered through celite-bed and washed with methanol. Thefiltrate was concentrated under reduced pressure to obtainIntermediate-AA114 which was used in the next step without furtherpurification. (0.250 g, 36%). MS (ES): m/z 218.2 [M+H]⁺

Synthesis of4-(6-amino-4-((dimethylamino)methyl)pyridin-3-yl)tetrahydro-2H-pyran-4-ol(Intermediate-AA115)

Step-1 Synthesis of tert-butyl (5-bromo-4-cyanopyridin-2-yl)carbamate(Intermediate-AA115-2)

To a solution of Intermediate-AA115-1 (25.0 g, 126.26 mmol) in DCM (250mL) were added DMAP (3.0 g, 25.25 mmol, 0.2 eq) and triethylamine (53mL, 378.78 mmol, 3.0 eq) at 0° C. After 20 min, di-tert-butyldicarbonate (35 mL, 151.51 mmol, 1.2 eq) was added dropwise. Afterstirring at RT for 16 h. the reaction mixture poured into ice cold waterwhereby a solid precipitated. The solid was collected and purified bycolumn chromatography eluting with 10% gradient of ethyl acetate inhexane to afford Intermediate-AA115-2 (15.0 g, 39.85%), MS (ES): m/z298.01 [M+H]⁺

Step-2 Synthesis of tert-butyl(4-(aminomethyl)-5-bromopyridin-2-yl)carbamate (Intermediate-AA115-3)

To a suspension of Raney Ni (pre-washed with methanol) (5 g) inMethanolic ammonia (13% w/w in methanol) (100 ml) was addedIntermediate-AA115-2 (15.0 g, 50.33 mmol, 1.0 eq) in THF (50 mL). Afterstirring under hydrogen atmosphere at RT for 4 h, the reaction mixturewas filtered through celite bed and washed with methanol. The filtratewas concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 25% ethyl acetate gradient in hexaneto afford Intermediate-AA115-3 (10.0 g, 65.78%), MS (ES): m/z 303.04[M+H]⁺

Step-3 Synthesis of tert-butyl(5-bromo-4-((dimethylamino)methyl)pyridin-2-yl)carbamate(Intermediate-AA115-4)

To a solution of Intermediate-AA115-3 (10.0 g, 33.11 mmol) in methanol(100 mL) were added formaldehyde (1.8 mL, 49.66 mmol, 1.5 eq) and aceticacid (0.4 mL, 8.27 mmol, 0.25 eq). After 30 min, sodium cyanoborohydride(2.4 g, 39.73 mmol, 1.2 eq) was added portion wise. After stirring at RTfor 1 h, the reaction mixture was concentrated under reduced pressure toremove methanol to get solid precipitate which was purified by columnchromatography eluting with 10% ethyl acetate gradient in hexane toafford Intermediate-AA115-4 (8.0 g, 73.20%), MS (ES): m/z 330.08 [M+H]⁺

Step-4 Synthesis of tert-butyl(4-((dimethylamino)methyl)-5-(4-hydroxytetrahydro-2H-pyran-4-yl)pyridin-2-yl)carbamate(Intermediate-AA115-5)

To a solution of Intermediate-AA115-4 (8.0 g, 24.24 mmol) in dry THF (80mL) at −76° C. added slowly dropwise n-butyllithium 2.5M in hexane (24mLg, 60.6 mmol, 2.5 eq). After stirring for 1 h at −76° C.,tetrahydro-4H-pyran-4-one (4.1 g, 41.20 mmol, 1.7 eq) was added. Afterstirring for 1 h, the reaction mixture transferred into ice cold water(200 mL) and extracted with ethyl acetate (2×100 mL). The combinedorganic extracts were washed with brine (100 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography eluting with 1% methanol gradient inDCM to afford Intermediate-AA115-5 (0.8 g, 10.40%), MS (ES): m/z 352.2[M+H]⁺

Step-5 Synthesis of4-(6-amino-4-((dimethylamino)methyl)pyridin-3-yl)tetrahydro-2H-pyran-4-ol(Intermediate-AA115)

To a solution of Intermediate-AA115-4 (0.8 g, 2.27 mmol) in DCM (8 mL)at 0° C. was added 4M HCl in dioxane (3 mL). After stirring at RT for 1h, the reaction mixture was neutralized with saturated sodiumbicarbonate solution and extracted with 10% methanol in DCM (3×30 mL).The combine organic layer was concentrated under reduced pressure. Theresidue was purified by column chromatography eluting with 100% DCM toafford Intermediate-AA115 (0.450 g, 78.66%), MS (ES): m/z 252.17 [M+H]⁺

Synthesis of 1-(4-aminophenyl)piperidin-4-ol (Intermediate-AA116)

Step-1 Synthesis of 1-(4-nitrophenyl) piperidin-4-ol(Intermediate-AA116-2)

To a solution of piperidin-4-ol-HCl salt (1.07 g, 10.63 mmol, 1.5 eq) inDMF (15 mL) was added K₂CO₃ (2.93 g, 21.27 mmol, 3.0 eq). After stirringfor 30 min, 1-fluoro-4-nitrobenzene (1 g, 7.09 mmol) was added. Afterstirring at 80° C. for 1 h, the reaction mixture was diluted with water(70 mL) and extracted with DCM (100 mL×2). The combined organic layerwas dried over sodium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography to obtainIntermediate-AA116-2 (700 mg, 44.44%). MS (ES): m/z 222 [M+H]⁺

Step-2 Synthesis of 1-(4-aminophenyl)piperidin-4-ol (Intermediate-AA116)

To a suspension of Pd/C (350 mg) in methanol (5 mL), was addedIntermediate-AA16-3 (700 mg). After hydrogenating at atmosphericpressure at RT for 4 h, the reaction mixture was filtered throughcelite-bed and washed with methanol. The filtrate was concentrated underreduced pressure to obtain Intermediate-AA116 (450 mg, 69.36%). MS (ES):m/z=192 [M+H]⁺

Synthesis of 5-(1-morpholinoethyl)pyridin-2-amine (Intermediate-AA118)

Step-1 Synthesis of 4-(1-(6-bromopyridin-3-yl)ethyl)morpholine(Intermediate-AA118-2)

To a solution of Intermediate-AA118-1 (1.0 g, 5.0 mmol), morpholine(0.783 g, 9.0 mmol, 1.8 eq) and triethylamine (1.0 mL, 7.5 mmol, 1.5 eq)in dichloroethane (10 mL) was added sodium triacetoxyborohydride (1.6 g,8.0 mmol, 1.6 eq) portion wise. After stirring at RT for 16 h, thereaction was quenched with water (100 mL) and extracted into DCM (3×40mL). The combined organic layer was washed with brine (50 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography 25% ethyl acetate gradientin hexane to afford Intermediate-AA118-2 (0.7 g, 51.64%) as a yellowoil. MS (ES): m/z 272.03 [M+H]⁺

Step-2 Synthesis ofN-(5-(1-morpholinoethyl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate-AA118-3)

To a solution of Intermediate-AA118-2 (0.7 g, 2.58 mmol) in toluene (10mL) were added cyclopropanecarboxamide (0.263 g, 3.0 mmol, 1.2 eq) andCs₂CO₃ (2.0 g, 6.45 mmol, 2.5 eq). After degassing under N2 stream for15 min, Xantphos (0.149 g, 0.258 mmol, 0.1 eq) and Pd₂(dba)₃ (0.118 g,0.129 mmol, 0.05 eq) were added. After stirring at 100° C. for 1 h, thereaction mixture was cooled to RT, diluted with water (50 mL), andextracted with ethyl acetate (3×30 mL). The combined organic extractswere washed with brine (50 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 4% MeOH gradient in DCM to affordIntermediate-AA118-3 (0.6 g, 84.81%) as a brown solid. MS (ES):m/z=276.17 [M+H]⁺

Step-3 Synthesis of 5-(1-morpholinoethyl)pyridin-2-amine(Intermediate-AA118)

To a solution of Intermediate-AA118-3 (0.6 g, 2.17 mmol) in 1:1methanol:water (8 mL) was added sodium hydroxide (0.868 g, 21.7 mmol, 10eq). After stirring at reflux for 6 h, the reaction mixture was cooledto RT and concentrated under reduced pressure. The residue was purifiedby column chromatography eluting with 5% methanol in DCM to affordIntermediate-AA118 (0.280 g, 61.99%) as a brown solid. MS (ES):m/z=208.14 [M+H]⁺

Synthesis of tert-butyl1-(6-amino-4-methylpyridin-2-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate(Intermediate-AA119)

Step-1 Synthesis ofN-(6-bromo-4-methylpyridin-2-yl)cyclopropanecarboxamide(Intermediate-AA119-2)

To a solution of Intermediate AA119-1 (2 g, 10.8 mmol) in DCM (40 mL)with trimethylamine (3.27 g, 32.43 mmol, 3.0 eq) at 0° C. was addedcyclopropane carbonyl chloride (3.67 g, 43.2 mmol, 4 eq) dropwise. Afterstirring at RT for 2 h, the reaction was diluted with water (150 mL) andextracted with ethyl acetate (3×70 mL). The combined organic layer waswashed with brine (150 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography to afford Intermediate-AA119-2 (1 g, 73%). MS (ES): m/z255.2 [M+H]⁺

Step-2 Synthesis of tert-butyl1-(6-(cyclopropanecarboxamido)-4-methylpyridin-2-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate(Intermediate AA119-3)

To a solution of Intermediate-AA119-2 (1.5 g, 5.9 mmol) in dioxane (15mL) were added Intermediate AA119-4 (1.5 g, 7.08 mmol, 1.2 eq) andpotassium carbonate (2.44 g, 17.7 mmol, 3.0 eq). After degassing withnitrogen for 20 min, Pd₂(dba)₃ (538 mg, 0.59 mmol, 0.1 eq) and Xantphos(341 mg, 0.59 mmol, 0.1 eq) were added. After stirring at 100° C. for 4h, the reaction was diluted with water (100 mL) and extracted with ethylacetate (3×80 mL). The combined organic layer was wash with brine (100mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography to affordIntermediate-AA119-3 (1 g, 44%). MS (ES): m/z 387.23 [M+H]⁺

Step-3 Synthesis of tert-butyl1-(6-amino-4-methylpyridin-2-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate(Intermediate AA119)

To a solution of Intermediate-AA119-3 (0.850 g, 2.1 mmol) in methanol(10 mL) and water (3 mL) was added sodium hydroxide (0.878 g, 21 mmol,10.0 eq). After stirring at 60° for 16 h, the reaction mixture wasconcentrated under reduced pressure and extracted with 10% methanol inDCM (3×90 mL). The combined organic layers were washed with brine (80mL), dried over Na₂SO₄, filtered, concentrated under reduced pressure toafford Intermediate-AA119 which was used in the next step withoutfurther purification (0.6 g, 85%), MS (ES): m/z 318.20 [M+H]⁺

Synthesis of4-(6-amino-4-((dimethylamino)methyl)pyridin-3-yl)tetrahydro-2H-pyran-4-ol(Intermediate-AA122)

Step-1 Synthesis of 2-amino-5-bromoisonicotinonitrile(Intermediate-AA122-2)

To a solution of Intermediate-AA122-1 (20.0 g, 167.8 mmol) and N-bromosuccinimide (Crystalline) (29.9 g, 167.8 mmol) in acetonitrile (400 mL)was stirred at RT for 2 h. After completion of reaction, the reactionmixture was diluted with sodium thiosulfate solution (1.0 L) andextracted with ethyl acetate (1 L×3). The combined organic layer wasdried over sodium sulfate and concentrated under reduced pressure. Theresidue was purified by column chromatography eluting with 20% ethylacetate in hexane to afford Intermediate-AA122-2 (20.0 g, 60.16%) as ayellow solid. MS (ES): m/z=196.96[M+H]⁺

Step-2 Synthesis of tert-butyl (5-bromo-4-cyanopyridin-2-yl) carbamate(Intermediate-AA122-3)

To a solution of Intermediate-AA122-2 (16.5 g, 82.9 mmol) and DMAP (2.0g, 16.0 mmol, 0.2 eq) in THF (200 mL) and triethylamine (33 mL, 248.0mmol, 3.0 eq) at 0° C. was added di-tert-butyl dicarbonate (21.6 g, 99.4mmol, 1.2 eq). After stirring for 16 h at RT, the reaction mixture wasdiluted with water (500 mL) and extracted with ethyl acetate (3×200 mL).The combined organic extracts were washed with brine (150 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography eluting with 10% ethylacetate gradient in hexanes to afford Intermediate-AA122-3 (10.0 g,40.25%) as a white solid. MS (ES): m/z=297.1 [M+H]⁺

Step-3 Synthesis of tert-butyl (4-(aminomethyl)-5-bromopyridin-2-yl)carbamate (Intermediate-AA122-4)

To a suspension of Raney Ni (4 mL) in THF (150 mL) was addedIntermediate-AA122-3 (10.0 g, 33.55 mmol) followed by ammonia solution(18 mL). After hydrogenating at atmospheric atmosphere for 4 h, thereaction mixture was filtered through celite-bed and washed withmethanol. The filtrate was concentrated under reduced pressure to obtainIntermediate-AA122-4 (8.0 g, 78.93%). MS (ES): m/z 303.04 [M+H]⁺

Step-4 Synthesis of tert-butyl(5-bromo-4-((dimethylamino)methyl)pyridin-2-yl)carbamate(Intermediate-AA122-5)

To a solution of Intermediate-AA122-4 (8.0 g, 26.57 mmol) andformaldehyde (3.0 g, 99.0 mmol, 1.5 eq) in methanol (100 mL) was addedacetic acid (0.398 g, 6.64 mmol, 0.25 eq). After stirring at RT for 1 h,sodium cyanoborohydride (2.0 g, 318.2 mmol, 1.2 eq) was added portionwise. After stirring for 45 min at RT, the reaction mixture wasconcentrated, and the residue was suspended in water (100 mL). Theresulting solid was collected by filtration and further purified bycolumn chromatography eluting with 5% ethyl acetate gradient in hexanesto afford Intermediate-AA122-5 (2.6 g, 29.74%). MS (ES): m/z=331.07[M+H]⁺

Step-5 Synthesis of tert-butyl(4-((dimethylamino)methyl)-5-(4-hydroxytetrahydro-2H-pyran-4-yl)pyridin-2-yl)carbamate(Intermediate-AA122-6)

To a suspension of Intermediate-AA122-5 (0.5 g, 1.51 mmol) in THF (5 mL)at −78° C. under argon was added n-butyllithium (1.6M) (1.51 mL, 3.78mmol, 2.5 eq). After stirring at −78° C. for 1 h,tetrahydro-4H-pyran-4-one (0.257 g, 2.57 mmol, 1.7 eq) was added. Afterstirring −78° C. for 1 h, the reaction mixture was diluted with water(50 mL) and extracted with ethyl acetate (3×20 mL). The combined organicextracts were washed with brine (50 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 1% MeOH gradient in DCM to affordIntermediate-AA129-6, (0.15 g, 28.19%). MS (ES): m/z 352.22 [M+H]⁺

Step-6 Synthesis of4-(6-amino-4-((dimethylamino)methyl)pyridin-3-yl)tetrahydro-2H-pyran-4-ol(Intermediate-AA122)

To a solution of Intermediate-AA122-6 (0.3 g, 0.85 mmol) in DCM (3 mL)was added 4 M HCl in dioxane (3.0 mL) at RT. After stirring at RT for 16h, the reaction was diluted with water (30 mL), neutralized with NaHCO₃,and extracted with ethyl acetate (3×30 mL). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated under reducedpressure to obtain Intermediate-AA122 (0.15 g, 69.92%): m/z=252.17[M+H]⁺

Synthesis of 1-(6-aminopyridin-3-yl)-3-(morpholinomethyl)piperidin-3-ol(Intermediate-AA123)

Step-1 Synthesis of tert-butyl3-hydroxy-3-(morpholinomethyl)piperidine-1-carboxylate(Intermediate-AA123-2)

A solution of Intermediate-AA123-1 (1.7 gm, 7098 mmol,1.0 eq) in ethanol(20 mL), was added morpholine (1.38 gm, 15.9 mmol,2.0 eq). Afterstirring at 80° C. for 2 h, the reaction mixture was diluted with water(50 mL) and extracted with DCM (3×30 mL). The combined organic extractswere washed with brine (60 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure affording Intermediate-AA123-2 (1.7g, 71.1%) which was used in the next step without further purification.MS (ES): m/z=301.5[M+H]⁺

Step-2 Synthesis2,2,2-trifluoro-1-(3-hydroxy-3-(morpholinomethyl)-1I4-piperidin-1-yl)ethan-1-one(Intermediate-AA123-3)

To a solution of Intermediate-AA123-2 (5.0 g, 16.66 mmol) in DCM (50mL), at 0° C. was added dropwise TFA (15 mL). After stirring at sametemperature. Reaction mixture was stirred at RT for 1 h, the reactionmixture was diluted with water (80 mL) and sodium bicarbonate solution(50 mL) and extracted with DCM (3×80 mL). The combined organic extractswere washed with brine (150 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was triturated by etherand methanol to afford Intermediate-AA123-3 (6.0 g, 89%). MS (ES):m/z=298.3 [M+H]⁺

Step-3 Synthesis of3-(morpholinomethyl)-1-(6-nitropyridin-3-yl)piperidin-3-ol(Intermediate-AA123-4)

To a solution of Intermediate-AA123-3 (1.7 gm, 52.28 mmol, 3.0 eq) inDMSO were added Intermediate-AA30-1 (2.5 gm, 17.6 mmol) and DIPEA (22.0ML, 211 mmol, 7.0 eq). After stirring at 110° C. for 4 h, the reactionmixture was diluted with water (100 mL) and extracted with ethyl acetate(3×80 mL). The combined organic extracts were washed with brine (100mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography eluting with2 to 3% methanol gradient in DCM to afford Intermediate-AA123-6 (4.0 g,70.22%). MS (ES): m/z=323.1[M+H]⁺

Step-4 Synthesis of1-(6-aminopyridin-3-yl)-3-(morpholinomethyl)piperidin-3-ol(Intermediate-AA123)

To a suspension of 10% palladium on carbon (0.7 g) in methanol (15 mL)was added Intermediate-AA123-4 (1.4 g, 4.76 mmol). After stirring underhydrogen at atmospheric pressure for 4 h. the reaction mixture wasfiltered through Celite-bed and washed with methanol. The filtrate wasconcentrated under reduced pressure to obtain Intermediate-AA123 (1.2 g,86.76%) which was used in the next step without further. MS (ES): m/z293.19[M+H]⁺

Synthesis of tert-butyl1-(6-aminopyrazin-2-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate(Intermediate-AA124)

Step-1 Synthesis of N-(6-chloropyrazin-2-yl)cyclopropanecarboxamide(AA124-2)

To a solution of Intermediate-AA124-1 (2 g, 1.54 mmol) in DCM (16 mL)and trimethylamine (6.43 mL, 4.620 mmol, 3 eq) was added cyclopropanecarbonyl chloride (6.4 g, 6.17 mmol, 4 eq). After stirring at RT for 2h, the reaction mixture was diluted with water (30 mL) and extractedwith DCM (3×80 mL). The combined organic extracts were washed with brine(50 mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure to afford Intermediate-AA124-2 which was use as such for nextstep. (1.5 g, 49.16%) MS (ES): m/z=197 [M+H]⁺

Step-2 Synthesis oftert-butyl1-(6-(cyclopropanecarboxamido)pyrazin-2-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate(Intermediate-AA124-3)

To a solution of tert-butylhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (1 g) in DMSO (15 mL),were added K₂CO₃ (2.93 g, 21.02 mmol, 3 eq) followed by TBAI (0.387 g,2.12 mmol, 0.3 eq). After stirring at RT for 15 min,Intermediate-AA124-2 (1.4 g, 7.08 mmol, 1 eq) was added. After stirringat 100° C. for 16 h, the reaction mixture was diluted with water (30 mL)and extracted with ethyl acetate (3×40 mL). The combined organicextracts were wash with brine (50 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 0-50% ethyl acetate gradient in hexane toafford Intermediate-AA124-3 (850 mg, 44.98%). MS (ES): m/z=373.4 [M+H]⁺

Step-3 Synthesis of tert-butyl1-(6-aminopyrazin-2-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate(Intermediate-AA124)

To a solution of Intermediate-AA124-3 (0.500 g, 1.33 mmol, 1 eq) in MeOH(5 mL), was added a solution of NaOH (1.07 g, 26.70 mmol, 20 eq) inwater (4 mL). After stirring at 80° C. for 16 h, the reaction mixturewas diluted with water (40 mL) and extracted with ethyl acetate (3×40mL). The combined organic extracts were washed with brine (50 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography eluting with 0-50% ethylacetate gradient in hexane to afford Intermediate-AA124 (320 mg, 78%).MS (ES): m/z=305.4 [M+H]+.

Synthesis of 1-(4-(6-aminopyridin-3-yl)morpholin-2-yl)cyclopropan-1-ol(Intermediate-AA125)

Step-1 Synthesis of tert-butyl 2-(1-hydroxycyclopropyl)morpholine-4-carboxylate (Intermediate-AA125-2)

To a solution of Intermediate-AA125-1 (10 g, 38.61 mmol) in THF (100 mL)at RT were added titanium(IV) isopropoxide (16 mL, 54.05 mmol, 1.4 eq)and EtMgBr (3M) (39 mL, 2.8 eq) dropwise. After stirring at RT for 1 h,the reaction mixture was quenched with aq NH₄C1 solution (100 mL) andextracted with ethyl acetate (3×80 mL). The combined organic extractswere washed with brine (100 mL) and dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 0-14% ethyl acetate gradient in hexane toafford Intermediate-AA125-2 (1.2 g) MS (ES): m/z=243 [M+H]⁺

Step-2 Synthesis of 1-(morpholin-2-yl)cyclopropan-1-ol(Intermediate-AA125-3)

To a solution of Intermediate-AA125-2 (2.5 g, 10.28 mmol) in DCM (25 mL)was added TFA (3.9 mL, 51.44 mmol, 5 eq) dropwise. After stirring at RTfor 30 min, the reaction was concentrated to afford Intermediate-AA125-3which was used as such for next step. (2.1 g) MS (ES): m/z=143 [M+H]⁺

Step-3 Synthesis of1-(4-(6-nitropyridin-3-yl)morpholin-2-yl)cyclopropan-1-ol(Intermediate-AA125-4)

To a solution of Intermediate-AA125-3 (2 g, 13.98 mmol, 1 eq) in DMSO(20 mL) was added 5-fluoro-2-nitropyridine (2.9 g, 20.97 mmol, 1.5 eq)and DIPEA (9.416 mL, 69.9 mmol, 5 eq). After stirring at 100° C. for 2h, the reaction mixture was diluted with water (20 mL) and extractedwith ethyl acetate (3×30 mL). The combined organic extracts were washedwith brine (30 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with 0-4% methanol gradient in DCM to affordIntermediate-AA125-4. (1.7 g). MS (ES): m/z=265 [M+H]⁺

Step-4 Synthesis of1-(4-(6-aminopyridin-3-yl)morpholin-2-yl)cyclopropan-1-ol(Intermediate-AA125)

To a suspension of 10% palladium on carbon (0.9 g) in methanol (10 mL)was added Intermediate-AA125-4 (1.8 g, 6.79 mmol). After stirring underhydrogen gas at atmospheric pressure at RT for 3 h, the reaction mixturewas filtered through Celite-bed and washed with methanol. The filtratewas concentrated under reduced pressure to afford Intermediate-AA125(1.9 g) as a brown solid which was use in the next step without furtherpurification. MS (ES): m/z=235.2 [M+H]⁺

Synthesis of 1-(6-aminopyridin-3-yl)-4-methoxypiperidin-4-yl)methanol(Intermediate-AA126)

(1-(6-aminopyridin-3-yl)-4-methoxypiperidin-4-yl)methanol (IntermediateAA126) was prepared from commercial 5-Fluoro-2-nitropyridine(Intermediate AA30-1) and (4-methoxypiperidin-4-yl)methanol in a similarfashion to that described5-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-2-amine(Intermediate AA30) (General process intermediate AA30) (0.300 g, 67%).MS (ES): m/z 239.23 [M+H]⁺

Synthesis of tert-butyl3-((6-amino-3-methylpyridin-2-yl)(methyl)amino)azetidine-1-carboxylate(Intermediate-AA128)

Step-1 Synthesis of tert-butyl3-((6-chloro-3-methylpyridin-2-yl)amino)azetidine-1-carboxylate(Intermediate-AA128-2)

To a solution of Intermediate-AA128-1 (0.5 g, 2.42 mmol) in dioxane (6mL) were added tert-butyl 3-aminoazetidine-1-carboxylate (0.417 g, 2.42mmol, 1 eq) and Cs₂CO₃ (1.56 g, 4.84 mol, 3.0 eq). After degassing underN2 stream for 20 min, Pd₂(dba)₃ (0.111 g, 0.121 mmol, 0.05 eq) andXantphos (0.140 g, 0.242 mmol, 0.1 eq) were added. After stirring at100° C. and for 1 h, the reaction mixture was cooled at RT and dilutedethyl acetate (100 mL) and water (50 mL). The organic layer wascollected, and the aqueous phase was extracted with ethyl acetate (2×30mL). The combined organic extracts were washed with brine (20 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography (0-50% gradient elutionEtOAc in hexane). The isolated solid was triturated with diethyl etherand the resulting solid was collected by filtration to afford the titlecompound Intermediate-AA128-2 (240 mg, 34.5%). MS (ES): m/z=297.12[M+1]+

Step-2 Synthesis of tert-butyl3-((6-chloro-3-methylpyridin-2-yl)(methyl)amino)azetidine-1-carboxylate)(Intermediate-AA128-3)

To a solution of Intermediate-AA128-2 (0.2 g, 0.67 mmol, 1 eq.) in DMF(30 mL) was added sodium hydride (77 mg, 3.3 mmol, 5 eq). After stirringfor 1 h, methyl iodide (113 mg, 0.80 mmol, 1.2 eq) was added dropwiseover a 30 min period. After stirring for 1 h at RT, the reaction wasquenched with water (30 mL) and extracted into DCM (3×40 mL). Thecombined organic layer was washed with brine, passed through ahydrophobic filter, and evaporated under reduced pressure. The residuewas purified by silica gel chromatography using 30% EtOAc:Hexane toafford Intermediate-AA128-3 (120 mg, 47%). MS (ES): m/z 311.1 [M+H]⁺.

Step-3 & Step-4. Synthesis of tert-butyl3-((6-amino-3-methylpyridin-2-yl)(methyl)amino)azetidine-1-carboxylate(Intermediate-AA128)

To a solution of Intermediate-AA128-3 (200 mg, 0.60 mmol) in dioxanewere added cyclopropanecarboxamide (102 mg, 10.3 mmol, 2 eq) and Cs₂CO₃(580 mg, 1.8 mmol, 3.0 eq). After degassing under N2 stream for 20 min,Pd₂(dba)₃ (54 mg, 0.06 mmol, 0.1 eq) and Xantphos (35 mg, 0.06 mmol, 0.1eq) were added. After stirring at 100° C. for 12 h, the reaction mixturewas cooled at RT and diluted DCM (100 mL) and water (50 mL). The organiclayer was collected, and the aqueous phase was extract with DCM (2×80mL). The combined organic extracts were washed with brine (20 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography (10% gradient elution DCMin MeOH). The residue obtained was then triturated with diethyl etherand the resulting solid was collected by filtration to afford thecompound tert-butyl3-((6-(cyclopropanecarboxamido)-3-methylpyridin-2-yl)(methyl)amino)azetidine-1-carboxylate(200 mg). To a solution of tert-butyl3-((6-(cyclopropanecarboxamido)-3-methylpyridin-2-yl)(methyl)amino)azetidine-1-carboxylate(200 mg, 0.55 mmol, 1 eq.) in methanol: H₂O (2:1 mL) was added solutionof NaOH (111 mg, 2.77 mmol, 5 eq.). After stirring for 2.5 h at 70° C.,the reaction mixture was evaporated, diluted with water, and extractedwith DCM (100 mL×3). The combined organic layers were evaporated toafford the title compound (Intermediate-AA128) as a white solid whichwas used as is. (650 mg, 59%). MS (ES): m/z 265.3[M+H]+

Synthesis of5-(4-(2-(dimethylamino)ethoxy)tetrahydro-2H-pyran-4-yl)pyridin-2-amine(Intermediate-AA129)

Step-1 Synthesis of2-44-(6-bromopyridin-3-yl)tetrahydro-2H-pyran-4-yl)oxy)-N,N-dimethylethan-1-amine(Intermediate-AA129-1)

To a solution of Intermediate AA57-2 (4 g, 15 mmol, 1 eq.) in DMF (30mL) was added sodium hydride (1.86 g,75 mmol, 5 eq). After stirring atRT for 1 h, 2-chloro-N, N-dimethylethan-1-amine (4.32 g,30 mmol, 2 eq)was added dropwise over a 30 min period. After stirring for 12 h at RT,the reaction was quenched with water (300 mL) and extracted into DCM(3×400 mL). The combined organic layer was washed with brine, passedthrough a hydrophobic filter, and evaporated in vacuum. The residue waspurified by silica gel chromatography using 10% MeOH: DCM to affordIntermediate-AA129-1 (1.1 g, 19.6%). MS (ES): m/z 328.03 [M+H]⁺

Step-2 Synthesis ofN-(5-(4-(2-(dimethylamino)ethoxy)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate-AA129-2)

To a solution of Intermediate-AA129-1 (1.4 g, 4.2 mmol) in dioxane wereadded cyclopropanecarboxamide (0.72 g, 8.4 mmol, 2 eq), and Cs₂CO₃ (3 g,7.5 mol, 3.0 eq). After degassing under N2 stream for 15 min, Pd₂(dba)₃(0.380 g, 0.42 mmol, 3 eq) and Xantphos (0.242 g, 0.42 mmol, 0.1 eq)were added. After stirring at 100° C. for 12 h, the reaction mixture wascooled to RT and diluted with DCM (100 mL) and water (50 mL). Theorganic layer was collected, and the aqueous phase was extract with DCM(2×80 mL). The combined organic extracts were washed with brine (20 mL),dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by column chromatography (10% gradient elutionDCM in MeOH). The residue obtained was then triturated with diethylether and the resulting solid was collected by filtration to afford thetitle compound Intermediate-AA129-2 (1.4 g, 98.74%). MS (ES): m/z333.43[M+H]⁺

Step-3 Synthesis of5-(4-(2-(dimethylamino)ethoxy)tetrahydro-2H-pyran-4-yl)pyridin-2-amine(Intermediate-AA129)

To a solution of Intermediate-AA129-2 (1.4 g, 4.2 mmol, 1 eq.) inmethanol:H₂O (20:10 mL) was added solution of NaOH (3.3 g, 80 mmol, 20eq.). After stirring for 2.5 h at 70° C., the reaction solvent wasevaporated, diluted with water (100 mL), and extracted with DCM (100mL×3). The organic phase was evaporated and dried over Na₂SO₄ to affordIntermediate-AA129 (650 mg, 59%) as a white solid. MS (ES): m/z265.3[M+H]⁺

Synthesis of tert-butyl(2-(4-(6-aminopyridin-3-yl)morpholin-2-yl)propan-2-yl)carbamate(Intermediate-AA130)

Step-1 Synthesis of tert-butyl(2-(4-benzylmorpholin-2-yl)propan-2-yl)carbamate (Intermediate AA130-1)

To a solution of Intermediate-AA93-2 (8 g, 34 mol) in THF:MeOH (80:20mL) were added triethyl amine (5.1 g, 51 mol, 1.5 eq) and Boc-anhydride(8.1 g, 37.4 mol, 1.1 eq) in portions. After stirring at RT for 12 h,the reaction was quenched with water (300 mL) and extracted into ethylacetate (3×400 mL). The combined organic layer was washed with brine,passed through a hydrophobic filter, and evaporated in vacuum. Theresidue was purified by silica gel chromatography using 1% EtOAc:hexaneto afford Intermediate-AA130-1 (2.2 g, 19.6%). MS (ES): m/z 334.23[M+H]⁺

Step-2 Synthesis of tert-butyl (2-(morpholin-2-yl)propan-2-yl)carbamate(Intermediate AA130-2)

To a suspension of palladium hydroxide (2.1 g) in methanol (30 mL) wasadded Intermediate-AA130-1 (2.1 g, 6 mol). After stirring under hydrogenatmosphere at 70° C. for 10 h in autoclave under 20 psi, the reactionmixture was cooled at RT, filtered using celite bed and concentrated.The residue was used for next step without purification affordingIntermediate-AA130-2 (1.2 g, 78%), MS (ES): m/z 244.3[M+H]+

Step-3 Synthesis of tert-butyl(2-(4-(6-nitropyridin-3-yl)morpholin-2-yl)propan-2-yl)carbamate(Intermediate-AA130-3)

To a solution of Intermediate-AA130-2 (1.2 g, 4.8 mmol) in DMSO: DIPEA(10:5 mL) was added 5-fluoro-2-nitropyridine (0.69 g, 4.8 mmol, 1 eq).After stirring at 120° C. for 2 h, the reaction mixture was cooled at RTand diluted with ethyl acetate (100 mL) and water (50 mL). The organiclayer was collected, and the aqueous phase was extract with ethylacetate (2×30 mL). The combined organic extracts were washed with brine(20 mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography (50%gradient of EtOAc hexane). The residue obtained was then triturated withdiethyl ether and the resulting solid was collected by filtration toafford the title compound (Intermediate-AA130-3) (1.1 g, 61%). MS (ES):m/z=366.42 [M+1]+

Step-4 tert-butyl (2-(4-(6-aminopyridin-3-yl) morpholin-2-yl)propan-2-yl) carbamate (Intermediate-AA130)

To a solution of Pd(C) (1.1 g) in methanol (15 mL) was addedIntermediate-AA130-3 (1.1 g, 29 mmol). After stirring at RT for 12 h inH2 gas atmospheric pressure at atmospheric pressure, the reactionmixture was filtered through celite bed. The organic layer wasevaporated in vacuum to afford Intermediate-AA130 (900 mg, 88%) whichwas used as is, MS (ES): m/z=336.42 [M+1]+

Synthesis of 1-(6-aminopyridin-3-yl)-3-(morpholinomethyl)piperidin-3-ol(Intermediate-AA132)

Step-1 Synthesis ofN,N-dimethyl-1-(4-(6-nitropyridin-3-yl)morpholin-2-yl)methanamine(Intermediate-AA132-1)

To a stirred solution of 3-(morpholinomethyl)piperidin-3-ol (500 mg,3.47 mmol, 1 eq) in DMSO (6 mL) were added DIPEA (5 mL, 27.7 mmol, 8 eq)and 5-fluoro-2-nitropyridine (0.739 g, 5.2 mmol, 1.5 eq). After stirringat 120° C. for 4 h, the reaction was diluted with water (35 mL) andextracted with ethyl acetate (3×30 mL). The combined organic layer waswashed with brine (40 mL), dried with sodium sulfate, and concentratedunder reduced pressure. The residue was purified by columnchromatography to afford Intermediate-AA132-1) (500 mg, 54.16%). MS(ES): m/z 322.20 [M+H]⁺

Step-2 Synthesis of1-(6-aminopyridin-3-yl)-3-(morpholinomethyl)piperidin-3-ol(Intermediate-AA132)

To a suspension of 10% Pd/C (0.3 g) in methanol was addedIntermediate-AA132-1 (0.5 g). After stirring under hydrogen gas atatmospheric pressure for 2 h, the reaction was filtered through celitebed and washed with methanol. The solvent was concentrated under reducedpressure to afford Intermediate-AA132 (300 mg, 67%). MS (ES): m/z 293.38[M+H]⁺.

Synthesis of tert-butyl(2-(4-(6-aminopyridin-3-yl)morpholin-2-yl)propan-2-yl)(methyl)carbamate(Intermediate-AA133)

Step-1 Synthesis of tert-butyl(2-(4-benzylmorpholin-2-yl)propan-2-yl)(methyl)carbamate(Intermediate-AA133-1)

To a solution of Intermediate-AA130-1 (10.0 g) and formaldehyde (2.56 g,2.0 eq) in dichloroethane (100 mL) was added trimethylamine (12 mL,85.46 mmol, 2.0 eq). After stirring at RT for 1 h. sodiumtriacetoxyborohydride (18.1 g, 85.46 mmol, 2.0 eq) was added in portion.After stirring for 16 h at RT, the reaction mixture was diluted withwater (200 mL) and sodium bicarbonate solution (100 mL) and extractedwith DCM (3×80 mL). The combined organic extracts were washed with brine(150 mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography eluting with3% methanol gradient in DCM to afford Intermediate-AA133-1) (4.0 g,35.72%) MS (ES): m/z=349.5 [M+H]⁺

Step-2 Synthesis of tert-butylmethyl(2-(morpholin-2-yl)propan-2-yl)carbamate (Intermediate-AA133-2)

To a suspension of 20% palladium hydroxide on carbon (2.0 g) in methanol(20 mL) was added Intermediate-AA133-1 (4.0 g). After stirring underhydrogen gas at atmospheric pressure at RT for 16 h, the reactionmixture was filtered through celite-bed and washed with methanol. Thefiltrate was concentrated under reduced pressure to affordIntermediate-AA133-2 (1.8 g, quantitative). MS (ES): m/z 258.36 [M+H]⁺

Step-3 Synthesis of tert-butylmethyl(2-(4-(6-nitropyridin-3-yl)morpholin-2-yl)propan-2-yl)carbamate(Intermediate-AA133-3)

To a solution of Intermediate-AA133-2 (1.8 g, 10.46 mmol) and5-fluoro-2-nitropyridine (0.890 g, 6.27 mmol, 0.6 eq) in DMSO (20 mL)was added dropwise N-ethyl-N-isopropylpropan-2-amine (7.1 mL, 41.84mmol, 3.0 eq). After stirring at 120° C. for 2 h, the reaction mixturewas diluted with water (100 mL) and extracted with ethyl acetate (3×80mL). The combined organic extracts were washed with brine (100 mL),dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by column chromatography eluting with 2%methanol in DCM to afford Intermediate-AA133-3 (1.4 g, 45.52%). MS (ES):m/z=381.2 [M+H]⁺

Step-4 Synthesis of tert-butyl(2-(4-(6-aminopyridin-3-yl)morpholin-2-yl)propan-2-yl)(methyl)carbamate(Intermediate-AA133)

To a suspension of 10% palladium on carbon (0.7 g) in methanol (15 mL)was added Intermediate-AA133-3 (1.4 g, 4.76 mmol). After stirring underhydrogen gas at atmospheric pressure at RT for 4 h, the reaction mixturewas filtered through Celite-bed and washed with methanol. The filtratewas concentrated under reduced pressure to afford Intermediate-AA133.which was used in the next step without further purification. (1.2 g,quantitative yield). MS (ES): m/z 351.2 [M+H]⁺

Synthesis of 1-(6-aminopyridin-3-yl)-4-(1-methylpyrrolidin-2-yl)piperidin-4-ol (Intermediate-AA134)

Step-1 Synthesis of benzyl 4-oxopiperidine-1-carboxylate (IntermediateAA134-3)

To a solution of piperidin-4-one (25.0 g, 185.18 mmol) and benzylcarbonochloridate (35 mL, 222.22 mmol, 1.2 eq) in 1,4-dioxane (200 mL)was added sodium bicarbonate (46.6 g, 555.54 mmol, 3.0 eq) and water(170 mL). After stirring at RT for 3 h, the reaction mixture was dilutedwith water (1000 mL) and extracted with ethyl acetate (3×150 mL)/Thecombined organic extracts were washed with brine (500 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography eluting with 40% ethyl acetategradient in hexane to afford Intermediate-AA134-3 (20.0 g, 34.00%), MS(ES): m/z 234.1 [M+H]⁺

Step-2 Synthesis of benzyl4-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-4-hydroxypiperidine-1-carboxylate(Intermediate AA134-5)

To a solution of tert-butyl pyrrolidine-1-carboxylate (12.0 g, 70.17mmol) in THF (400 mL) at −78° C. was added sec-Butyl lithium (1.3M incyclohexane) (65 mL, 84.20 mmol, 1.2 eq). After stirring at −78° C. for3 h, Intermediate AA143-3 (16.3 g, 70.17 mmol) in THF was added dropwiseinto the reaction mixture at −78° C. After stirring for 2 h at −78° C.and for 16 hr at RT, the reaction mixture was diluted with water (700mL) and extracted with ethyl acetate (3×200 mL). The combined organicextracts were washed with brine (500 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 20% ethyl acetate gradient in hexaneto afford Intermediate-AA134-5 (6.7 g, 23.64%), MS (ES): m/z 405.2[M+H]⁺

Step-3 Synthesis of benzyl4-hydroxy-4-(pyrrolidin-2-yl)piperidine-1-carboxylate (IntermediateAA134-6)

To a solution of Intermediate-AA134-5) (6.7 g, 16.58 mmol) in DCM (70mL) at 0° C. was added HCl in dioxane (35 mL). After stirring at RT for1 h, the reaction was neutralized with saturated sodium bicarbonatesolution and extracted with DCM (3×150 mL). The combined organic layerwas concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 6% gradient elution in DCM to affordIntermediate-AA134-6 (1.09 g, 19.83%), MS (ES): m/z 305.1 [M+H]⁺

Step-4 Synthesis of benzyl4-hydroxy-4-(1-methylpyrrolidin-2-yl)piperidine-1-carboxylate(Intermediate AA134-8)

To a solution of Intermediate-AA134-6 (1.0 g, 3.28 mmol) in methanol (10mL), were added formaldehyde (10 mL) and acetic acid (5 mL). Afterstirring for 1 h at RT, sodium cyanoborohydride (0.247 g, 3.93 mmol, 1.2eq) was added. After stirring for 16 h at RT, the reaction mixture wasconcentrated under reduced pressure, diluted with water (80 mL), andextracted with 10% methanol in DCM (3×30 mL). The combined organicextracts were washed with brine (80 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 3% methanol gradient in DCM to affordIntermediate-AA134-8 (0.7 g, 66.92%), MS (ES): m/z 319.2 [M+H]⁺

Step-5 Synthesis of 4-(1-methylpyrrolidin-2-yl)piperidin-4-ol(Intermediate-AA134-9)

To a solution of Intermediate-AA134-8 (0.630 g, 2.20 mmol) in methanol(10 mL) was added 10% palladium on charcoal (0.3 g). After stirringunder hydrogen at atmospheric pressure for 16 h at RT, the reactionmixture was filtered through celite-bed and washed with methanol. Thefiltrate was concentrated under reduced pressure to obtainIntermediate-AA134-9 which was used in the next step without furtherpurification. (0.450 g, quantitative). MS (ES): m/z 185.1 [M+H]⁺.

Step-6 Synthesis of4-(1-methylpyrrolidin-2-yl)-1-(6-nitropyridin-3-yl)piperidin-4-ol(Intermediate-AA134-10)

To a solution of 5-fluoro-2-nitropyridine (0.6 g, 4.22 mmol) andIntermediate-AA134-9 (0.78 g, 4.22 mmol) in DMSO (6 mL), were addedpotassium carbonate (1.7 g, 12.66 mmol, 3.0 eq) and tetrabutylammoniumiodide (0.155 g, 0.422 mmol, 0.1 eq). After stirring at 120° C. for 3 h,the reaction mixture was diluted with water (50 mL) and extracted with10% methanol in DCM (3×30 mL). The combined organic extracts were washedwith brine (50 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with 3% methanol gradient in DCM to afford Intermediate-AA134-10(0.3 g, 38.65%), MS (ES): m/z 307.1 [M+H]⁺

Step-7 Synthesis of1-(6-aminopyridin-3-yl)-4-(1-methylpyrrolidin-2-yl)piperidin-4-ol(Intermediate-AA134)

To a solution of Intermediate AA134-10 (0.3 g, 0.98 mmol) in methanol (5mL) was added 10% palladium on charcoal (0.15 g). After stirring underhydrogen gas at atmospheric pressure for 16 h at RT, the reactionmixture was filtered through celite-bed and washed with methanol. Thefiltrate was concentrated under reduced pressure to affordIntermediate-AA134 which was used in the next step without furtherpurification. (0.250 g, quantitative). MS (ES): m/z 277.2 [M+H]⁺.

Synthesis of6-((dimethylamino)methyl)-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyridin-2-amine(Intermediate-AA135)

Step-1 Synthesis of6-chloro-3-(4-oxa-7-azaspiro[2.5]octan-7-yl)picolinaldehyde(Intermediate AA135-2)

To a solution of Intermediate AA135-1 (0.9 g, 5.66 mmol) and4-oxa-7-azaspiro[2.5]octane (0.843 g, 5.66 mmol) in DMF (10 mL) wasadded potassium carbonate (2.3 g, 16.98 mmol, 3.0 eq). After stirring at100° C. for 1 h, the reaction mixture was cooled to RT, diluted with icecold water (50 mL) and extracted with ethyl acetate (3×20 mL). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography eluting with 20% ethyl acetategradient in hexane to obtain Intermediate AA135-2 (1.0 g, 70.15%), MS(ES): m/z 253.07 [M+H]⁺

Step-2 Synthesis of1-(6-chloro-3-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyridin-2-yl)-N,N-dimethylmethanamine(Intermediate AA135-3)

To a solution of Intermediate AA135-2 (1.0 g, 3.96 mmol) in methanol (10mL) were add dimethylamine (2M in THF) (38.5 mL) and acetic acid (3.5mL) dropwise at RT. After stirring at RT for 1 h, the reaction mixturewas cooled to 0° C. and sodium triacetoxyborohydride (1.67 g, 7.92 mmol,2.0 eq) was added portion wise. After stirring at RT for 20 min, thereaction mixture was diluted with water (100 mL) and extracted with 10%methanol in DCM (3×40 mL). The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure to afford Intermediate AA135-3 (0.710 g, 63.67%), MS (ES): m/z282.13 [M+H]⁺

Step-3 Synthesis ofN-(6-((dimethylamino)methyl)-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA135-4)

To a solution of Intermediate AA135-3 (0.5 g, 1.77 mmol) in 1,4-Dioxane(5 mL) were added K₂CO₃ (0.732 g, 5.31 mmol, 3.0 eq) andcyclopropanecarboxamide (0.453 g, 5.33 mmol, 3.0 eq). After degassingunder N2 stream for 15 min, Xantphos (0.098 g, 0.17 mmol, 0.1 eq) andPd₂(dba)₃ (0.155 g, 0.17 mmol, 0.1 eq) were added. After stirring at110° C. for 16 h, the reaction mixture was cooled to RT, diluted withwater (50 mL), and extracted with ethyl acetate (3×20 mL). The combinedorganic extracts were washed with brine (50 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography eluting with 7% methanol gradient inDCM to afford Intermediate AA135-4 (0.350 g, 59.69%), m/z=331.2 [M+1]⁺

Step-4 Synthesis of6-((dimethylamino)methyl)-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyridin-2-amine(Intermediate AA135)

To a solution of Intermediate AA135-4 (0.350 g, 1.06 mmol) in methanol(8 mL) and water (2 mL) was added sodium hydroxide (0.424 g, 10.6 mmol,10.0 eq). After stirring at RT for 16 h, the reaction mixture wasdiluted with water (25 mL) and extracted with DCM (4×15 mL). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography eluting with 3% methanol gradient inDCM to afford Intermediate AA135 (0.170 g, 61.17%), m/z=263.1[M+1]⁺

Synthesis of3-(1-(6-aminopyridin-3-yl)piperidin-3-yl)-1-methylazetidin-3-ol(Intermediate-AA136)

Step-1 & Step-2 Synthesis of tert-butyl 3-hydroxy-3-(pyridin-3-yl)azetidine-1-carboxylate (Intermediate-AA136-3)

To magnesium metal (1.5 g, 63.29 mmol, 5 eq) in THF (8 mL) heated for 2min were added 1, 2 di-bromoethane (0.5 mL) and thenIntermediate-AA136-1 (2 g, 12.65 mmol) dropwise. After cooling to RT,tert-butyl 3-oxoazetidine-1-carboxylate (0.861 g, 5.06 mmol, 0.4 eq) wasadded. After stirring for 2 hr, the reaction was diluted with water (100mL), extracted with ethyl acetate, and concentrated in vacuo. Theresidue was purified by column chromatography to affordIntermediate-AA136-3 (1.3 g, 41%), MS (ES): m/z 250.30 [M+H]⁺.

Step-3 Synthesis of 3-(pyridin-3-yl) azetidin-3-ol (IntermediateAA136-4)

To a solution of Intermediate-AA136-3 (3.8 g, 15.18 mmol) in DCM (40 mL)was added 4M Dioxane HCl (15 mL, 4 eq) at 0° C. After stirring at RT for2 h, the residue was quenched in sodium bicarbonate (100 mL) andextracted with DCM (3×100 mL) to afford Intermediate-AA136-4 (2 g,87.72%) which was used as is, MS (ES): m/z 250.30 [M+H]⁺

Step-4 Synthesis of 1-methyl-3-(pyridin-3-yl)azetidin-3-ol (IntermediateAA136-5)

To a solution of Intermediate-AA136-4 (3 g, 2.1 mmol, 1 eq) in methanol(30 mL) was added formaldehyde (2 mL, 3.9 mmol, 1.9 eq). After stirringat RT for 30 min, acetic acid (3 mL, 1V) and NaCN(BH)₃ (2.5 g, 4.2 mmol,2 eq) were added. After stirring at 50° C. for 2 h, the solvent wasevaporated. The residue was purified by column chromatography elutedwith 7% methanol in DCM to afford Intermediate-AA136-5. (2.1 g, 60.97%),MS (ES): m/z 165.21 [M+H]⁺

Step-5 Synthesis of 1-methyl-3-(piperidin-3-yl)azetidin-3-ol(Intermediate AA136-6)

To a suspension of PtO2 (1 g) in acetic acid (10 mL) was addedIntermediate AA136-5 (2.1 g, 12.71 mmol, 1 eq). After stirring inautoclave at 20 psi hydrogen pressure at RT for 24 h, the reaction wasfiltered through celite and the bed washed with EtOAc. The filtrate wasevaporated under reduced pressure to afford Intermediate-AA136-6 (1.6 g,73.48%) which was used as is, MS (ES): m/z 170.14 [M+H]⁺

Step-6 Synthesis of1-methyl-3-(1-(6-nitropyridin-3-yl)piperidin-3-yl)azetidin-3-ol(Intermediate AA136-7)

To a solution of 5-bromo-2-nitro pyridine (1 g, 4.9 mmol, 1 eq) indioxane (10 mL) were added Intermediate-AA136-6 (837 mg, 4.9 mmol, 1 eq)and Cs₂CO₃(4.79 g, 14.76 mmol, 3 eq). After degassing with N2 stream for20 min, Pd₂(dba)₃ (0.450 mg, 0.4 mmol, 0.1 eq) and xantphos (0.560 mg,0.9 mmol, 0.2 eq) were added. After stirring at 110° C. for 2 h, thereaction was diluted with water and extracted with ethyl acetate. Thecombined organic solution was dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 10% methanol in DCM to affordIntermediate-AA136-7) (360 mg, 25%) as a yellow solid. MS (ES): m/z292.34 [M+H]⁺

Step-7 Synthesis of3-(1-(6-aminopyridin-3-yl)piperidin-3-yl)-1-methylazetidin-3-ol(Intermediate-AA136)

To a solution of Intermediate-AA136-7 (0.270 g, 0.923 mmol, 1.0 eq) inmethanol (3 mL) was added 10% palladium on charcoal (130 mg). Afterstirring with hydrogen gas at atmospheric pressure for 4 h at RT, thereaction mixture was filtered through celite-bed and washed withmethanol. The filtrate was concentrated under reduced pressure to affordIntermediate-AA136 which was used in the next step without furtherpurification. (200 mg, quantitative). MS (ES): m/z 262.36 [M+H]⁺.

Synthesis of tert-butyl6-(6-aminopyridin-2-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate(Intermediate-AA137)

Step-1 Synthesis of tert-butyl6-(6-nitropyridin-2-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate(Intermediate-AA137-1)

To a stirred solution of 2-chloro-6-nitropyridine (500 mg, 2.5 mmol, 1eq) in dioxane (5 mL) were added tert-butyl1,6-diazaspiro[3.3]heptane-1-carboxylate oxalate salt (480 mg, 3mmol,1.2 eq) and NaOtBu (0.726 g, 7.5 mmol, 3 eq). After degassing withN2 gas for 20 min, Pd₂(dba)₃ (0.230 mg, 0.25 mmol, 0.1 eq) and Ruphose(0.117 mg, 0.25 mmol, 0.1 eq) were added. After stirring at 110° C. for2 h, the reaction was diluted with water and extracted with ethylacetate. The organic layer was collected and dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography eluting with 2% methanol in DCM toafford Intermediate-AA137-1 (0.360 g, 35.20%) as a brown solid. MS (ES):m/z 320.35 [M+H]⁺

Step-2 Synthesis of tert-butyl6-(6-aminopyridin-2-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate(Intermediate AA137)

To a solution of Intermediate-AA37-1 (0.080 g, 0.25 mmol) in methanol (3mL) was added 10% palladium on charcoal (30 mg). After stirring underhydrogen gas at atmospheric pressure for 4 h at RT, the reaction mixturewas filtered through celite-bed and washed with methanol. The filtratewas concentrated under reduced pressure to afford Intermediate-AA137which was used in the next step without further purification. (60 mg,quantitative). MS (ES): m/z 290.37 [M+H]⁺.

Synthesis of tert-butyl1-(6-aminopyrazin-2-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate(Intermediate-AA138)

Step-1 Synthesis ofN-(6-bromo-4-methoxypyridin-2-yl)cyclopropanecarboxamide Intermediate(Intermediate-AA138-2)

To a solution of Intermediate-AA138-1 (4.0 g, 31.00 mmol) in DCM (40 mL)trimethylamine (13 mL, 93 mmol, 3.0 eq) at 0° C. was added cyclopropanecarbonyl chloride (12.8 g, 124 mmol, 4 eq) dropwise. After stirring atRT for 2 h, the reaction was diluted with water (200 mL) and extractedwith ethyl acetate (3×70 mL). The combined organic layer was washed withbrine (200 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with 10% ethyl acetate gradient in hexane to affordIntermediate-AA138-2 (3.5 g, 57.36%) as a yellow oil. MS (ES): m/z 271[M+H]⁺

Step-2 Synthesis of tert-butyl1-(6-(cyclopropanecarboxamido)-4-methoxypyridin-2-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate(Intermediate AA138-4)

To a solution of Intermediate-AA138-3 (1.5 g, 7.10 mmol) in DMSO (15 mL)were added tetra butyl ammonium iodide (0.785 g, 2.13 mmol, 0.3 eq) andpotassium carbonate (2.9 g, 21.3 mmol, 3.0 eq). After 15 min,Intermediate-AA139-2 (1.4 g, 71.0 mmol, 1.0 eq) was added. Afterstirring at 100° C. for 16 h, the reaction was diluted with water (100mL) and extracted with ethyl acetate (3×40 mL). The combined organiclayer was washed with brine (100 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography to afford Intermediate-AA138-4 (0.850 g, 32.13%) as ayellow oil. MS (ES): m/z 402.23 [M+H]⁺

Step-3 Synthesis of tert-butyl1-(6-amino-4-methoxypyridin-2-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate(Intermediate AA138)

To a solution of Intermediate-AA138-4 (0.850 g, 2.27 mmol) in methanol(10 mL) and water (3 mL) was added sodium hydroxide (0.9 g, 22.7 mmol,10.0 eq). After stirring at 60° for 16 h, the reaction mixture wasconcentrated under reduced pressure to remove methanol and extractedwith 10% methanol in DCM (3×70 mL). The combined organic layers werewashed with brine (80 mL), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure to afford Intermediate-AA138 which was used as is(0.6 g), MS (ES): m/z 306.19 [M+H]⁺

Synthesis of tert-butyl1-(6-aminopyrazin-2-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate(Intermediate-AA139)

Step-1 Synthesis of N-(6-chloropyrazin-2-yl)cyclopropanecarboxamide(Intermediate-AA139-2)

To a solution of Intermediate-AA139-1 (4.0 g, 31.00 mmol) in DCM (40 mL)and trimethylamine (13 mL, 93.0 mmol, 3.0 eq) at 0° C. was addedcyclopropane carbonyl chloride (12.8 g, 124 mmol, 4.0 eq) dropwise.After stirring at RT for 2 h, the reaction was diluted with water (200mL) and extracted with ethyl acetate (3×70 mL). The combined organiclayer was washed with brine (200 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography 10% ethyl acetate gradient in hexane to affordIntermediate-AA139-1 (3.5 g, 57.36%) as a yellow oil. MS (ES): m/z198.04 [M+H]⁺

Step-2 Synthesis of tert-butyl1-(6-(cyclopropanecarboxamido)pyrazin-2-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate(Intermediate AA139-4)

To a solution of Intermediate-AA139-3 (1.5 g, 7.10 mmol) in DMSO (15 mL)were added tetra butyl ammonium iodide (0.785 g, 2.13 mmol, 0.3 eq) andpotassium carbonate (2.9 g, 21.3 mmol, and 3.0 eq). After 15 min,Intermediate-AA139-2 (1.4 g, 7.10 mmol) was added. After stirring at100° C. for 16 h, the reaction was diluted with water (100 mL) andextracted with ethyl acetate (3×40 mL). The combined organic layer waswashed with brine (100 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography 50% ethyl acetate gradient in hexane to affordIntermediate-AA139-4) (0.850 g, 32.13%) as a yellow oil. MS (ES): m/z374.2 [M+H]⁺

Step-3 Synthesis of tert-butyl1-(6-aminopyrazin-2-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate(Intermediate AA139)

To a solution of Intermediate-AA139-4 (0.850 g, 2.27 mmol) in methanol(10 mL) and water (3 mL) was added sodium hydroxide (0.9 g, 22.7 mmol,10.0 eq). After stirring at 60° for 16 h, the reaction mixtureconcentrated under reduced pressure to remove methanol and extractedwith 10% methanol in DCM (3×70 mL). The combined organic layers werewashed with brine (80 mL), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure to afford Intermediate-AA139 (0.6 g) which wasused as is. MS (ES): m/z 306.19 [M+H]⁺

Synthesis of5-(2-(1-(dimethylamino)cyclopropyl)morpholino)pyridin-2-amine(Intermediate-AA140)

Step-1 tert-butyl 2-(dimethylcarbamoyl)morpholine-4-carboxylate.Intermediate (AA140-2)

To a solution of Intermediate-AA125-1 (10.0 g, 38.61 mmol) and dry THF(100 mL) were added dimethyl amine (2M in THF) (23 mLg, 46.33 mmol, 1.2eq) and trimethylaluminum (2M in THF) (28 mg, 57.91 mmol, 1.5 eq). Afterstirring at 70° C. for 16 h, the reaction mixture was cooled to RT,diluted with water (150 mL), and extracted with ethyl acetate (3×80 mL).The combined organic layers were washed with brine (80 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography eluting with 25% ethyl acetategradient in hexane to afford Intermediate-AA140-2 (6.5 g, 65.25%) as abrown solid. MS (ES): m/z=259.16 [M+H]⁺

Step-2 Synthesis of tert-butyl2-(1-(dimethylamino)cyclopropyl)morpholine-4-carboxylate (IntermediateAA140-3)

To a solution of ethyl magnesium bromide solution (1.0M in THF) (62 mL,62.98 mmol, 2.5 eq) in THF (70 mL) at −78° C. was added dropwisetitanium isopropoxide (7.6 mL, 25.19 mmol). After 5 min,Intermediate-AA140-2 (6.5 g, 25.19 mmol) was added/After stirring at 70°C. for 1 h, the reaction mixture cooled to RT, diluted with water (80mL), and extracted with ethyl acetate (3×40 mL). The combined organicextracts were washed with brine (90 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 25% ethyl acetate gradient in hexaneto afford Intermediate-AA140-3 (1.5 g, 22.05%) MS (ES): m/z=271.2[M+H]⁺

Step-3 Synthesis of N,N-dimethyl-1-(morpholin-2-yl)cyclopropan-1-amine(Intermediate AA140-4)

To a solution of Intermediate-AA140-3 (1.5 g, 5.55 mmol) in DCM (15 mL)was added 4 M HCl in dioxane (10 mL) at 0° C. After stirring at RT for30 min, the reaction was diluted with water (30 mL) and extracted with30% propane 2-ol in chloroform (4×30 mL). The combined organic layer wasdried over Na₂SO₄, filtered, and concentrated under reduced pressure toafford Intermediate-AA140-4 (0.8 g): m/z=171.15 [M+H]⁺

Step-4 Synthesis ofN,N-dimethyl-1-(4-(6-nitropyridin-3-yl)morpholin-2-yl)cyclopropan-1-amine(Intermediate AA140-5)

To a solution of Intermediate-AA140-4 (0.8 g, 4.70 mmol) and5-fluoro-2-nitropyridine (0.668 g, 4.70 mmol) in DMSO (8 mL), were addedN, N-diisopropylethylamine (2.4 mL, 14.1 mmol, 3.0 eq) andtetrabutylammonium iodide (0.173, 0.47 mmol, 0.1 eq). After stirring at120° C. for 2 h, the reaction mixture cooled to RT and diluted with icecold water whereby a solid material precipitated from solution. Thesolid was filtered and dried under high vacuum to affordIntermediate-AA140-5 (0.630 g, 45.86%) as a brown solid. MS (ES):m/z=293.16 [M+H]⁺

Step-5 Synthesis of5-(2-(1-(dimethylamino)cyclopropyl)morpholino)pyridin-2-amine(Intermediate-AA140)

To a solution of Intermediate-AA140-5 (0.630 g, 2.15 mmol) in methanol(7 mL) was added 10% palladium on charcoal (0.3 g). After stirring underhydrogen gas at atmospheric pressure for 4 h at RT, the reaction mixturewas filtered through celite-bed and washed with methanol. The filtratewas concentrated under reduced pressure to afford Intermediate-AA140which was used in the next step without further purification. (0.520 g).MS (ES): m/z 263.18 [M+H]⁺

Synthesis of 1-(6-aminopyridin-2-yl)-5-(azetidin-1-ylmethyl)piperidin-2-one (Intermediate-AA141)

Step-1 Synthesis of5-(hydroxymethyl)-1-(6-nitropyridin-2-yl)piperidin-2-one (IntermediateAA141-1)

To a solution of Intermediate-AA51-1 (500 mg, 1.76 mmol) in dioxane (5mL), were added 5-(hydroxymethyl)piperidin-2-one (334 mg, 2.1 mmol, 1.2eq) and K₂CO₃ (729 mg, 5.2 mmol, 3 eq). After degassing under N2 streamfor 20 min, Xantphos (0.090 g, 0.17 mmol, 0.1 eq) and Pd₂(dba)₃ (0.161g, 0.17 mmol, 0.1 eq) were added. After stirring at 100° C. for 1 h, thereaction mixture was cooled to RT, diluted with water (80 mL), andextracted with ethyl acetate (3×30 mL). The combined organic extractswere washed with brine (90 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography to afford Intermediate-AA141-1 (0.300 g, 37.23%). MS(ES): m/z=251.09 [M+H]⁺

Step-2 Synthesis of 1-(6-nitropyridin-2-yl)-6-oxopiperidin-3-yl)methyl4-methylbenzenesulfonate (Intermediate AA141-2)

To a solution of Intermediate-AA141-2 (400 mg, 1.58 mmol) in DCM (4 mL)were added triethylamine (0.66 mL, 4.76 mmol, 3 eq) and4-toluenesulfonyl chloride (0.904 m, 4.76 mmol, 3 eq). After stirring atRT for 5 h, the reaction diluted with water (40 mL) and extracted withethyl acetate (3×50 mL). The combined organic layers were washed withbrine (50 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatography toafford Intermediate-AA141-2 (300 mg, 46%). MS (ES): m/z 405.43 [M+H]⁺

Step-3 Synthesis of5-(azetidin-1-ylmethyl)-1-(6-nitropyridin-2-yl)piperidin-2-one(Intermediate AA141-3)

A solution of Intermediate-AA141-2 (200 mg, 49.2 mmol) in acetonitrile(3 mL), were added K₂CO₃ (271 mg, 1.9 mmol, 4.0 eq), and azetidine (56mg, 98.5 mmol, 2 eq). After stirring at 90° C. for 2 h, the reaction wasdiluted with water (20 mL) and extracted with ethyl acetate (2×50 mL).The combined organic layer was wash with brine (50 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography to afford Intermediate-AA141-3(200 mg, 50%) as a yellow oil. MS (ES): m/z 290.14 [M+H]⁺

Step-4 Synthesis of1-(6-aminopyridin-2-yl)-5-(azetidin-1-ylmethyl)piperidin-2-one(Intermediate-AA141)

To a suspension of 10% palladium on charcoal (0.300 g) was addedIntermediate-AA141-3) (600 mg). After stirring with hydrogen gas atatmospheric pressure for 2 h at RT, the reaction mixture was filteredthrough celite-bed and washed with methanol. The filtrate wasconcentrated under reduced pressure afford Intermediate-AA141 (200 mg,74.34%). MS (ES): m/z 260.34 [M+H]⁺

Synthesis of tert-butyl4-(6-aminopyridin-3-yl)hexahydropyrrolo[3,4-b][1,4]oxazine-6(2H)-carboxylate(Intermediate-AA142)

Step-1 Synthesis of tert-butyl3-bromo-4-(2-hydroxyethoxy)pyrrolidine-1-carboxylate (IntermediateAA142-2)

To a solution of Intermediate-AA-141 (3.0 g, 17.75 mmol) in ethyleneglycol (30 mL) was added N-Bromosuccinimide (3.2 g, 18.28 mmol, 1.03eq). After stirring at RT for 16 h, the reaction was quenched with water(150 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic layer was washed with brine (80 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography 1% methanol gradient in DCM to affordIntermediate-AA142-1 (4.9 g, 89.11%) as a yellow oil. MS (ES): m/z310.19 [M+H]⁺

Step-2 Synthesis of tert-butyl3-bromo-4-(2-(tosyloxy)ethoxy)pyrrolidine-1-carboxylate (IntermediateAA142-3)

To a solution of Intermediate-AA142-2 (4.9 g, 15.80 mmol) in toluene (30mL) with triethylamine (2.6 mL, 18.96 mmol, 1.2 eq) and DMAP (0.038 g,0.316 mmol, 0.02 eq) at 0° C. was added 4-toluenesulfonyl chloride (2.78mL, 18.96 mmol, 1.2 eq) dropwise. After stirring at RT for 16 h, thereaction was quenched with water (200 mL) and extracted with ethylacetate (3×80 mL). The combined organic layer was washed with brine (100mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography eluting with25% ethyl acetate gradient in hexane to afford Intermediate-AA142-3 (5.5g, 74.98%) as a yellow oil. MS (ES): m/z 465.06 [M+H]⁺

Step-3 Synthesis of tert-butyl4-benzylhexahydropyrrolo[3,4-b][1,4]oxazine-6(2H)-carboxylate(Intermediate AA142-4)

To a solution of Intermediate-AA142-3 (5.5 g, 11.82 mmol) in xylene (60mL) was added phenylmethanamine (3.7 g, 35.46 mmol, 3.0 eq). Afterstirring at 140° C. for 16 h, the reaction mixture was cooled to RT andconcentrated under reduced pressure. The residue diluted with water (150mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayer was washed with brine (100 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography 20% ethyl acetate gradient in hexane to affordIntermediate-AA142-4 (4.1 g, 95.46%) as a yellow oil. MS (ES): m/z319.20 [M+H]⁺

Step-4 Synthesis of tert-butylhexahydropyrrolo[3,4-b][1,4]oxazine-6(2H)-carboxylate (IntermediateAA142-5)

To a solution of Intermediate-AA142-4 (4.0 g, 12.57 mmol) in methanol(40 mL) was added 10% palladium on charcoal (2.0 g). After stirringunder hydrogen gas at atmospheric pressure for 16 h at RT, the reactionmixture was filtered through celite-bed and washed with methanol. Thefiltrate was concentrated under reduced pressure. The residue waspurified by column chromatography eluting with 5% methanol gradient inDCM to afford Intermediate-AA142-5 (1.7 g, 59.28%). MS (ES): m/z 229.15[M+H]⁺.

Step-5 Synthesis of tert-butyl4-(6-nitropyridin-3-yl)hexahydropyrrolo[3,4-b][1,4]oxazine-6(2H)-carboxylate(Intermediate-AA142-6)

To a solution of 5-bromo-2-nitropyridine (1.6 g, 7.88 mmol) andIntermediate-AA142-5 (2.1 g, 9.45 mmol, 1.2 eq) in toluene (20 mL) wasadded Cs₂CO₃ (5.1 g, 15.76 mmol, 2.0 eq). After degassing under N2stream for 15 min, Xantphos (0.45 g, 0.78 mmol, 0.1 eq) and Pd₂(dba)₃(0.360 g, 0.394 mmol, 0.05 eq) were added. After stirring at 100° C. for1 h, the reaction mixture was cooled to RT, diluted with water (80 mL),and extracted with ethyl acetate (3×30 mL). The combined organicextracts were washed with brine (90 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 3% methanol gradient in DCM to affordIntermediate-AA142-6 (1.7 g, 69.23%) as a brown solid. MS (ES):m/z=351.16 [M+H]⁺

Step-6 Synthesis of tert-butyl4-(6-aminopyridin-3-yl)hexahydropyrrolo[3,4-b][1,4]oxazine-6(2H)-carboxylate(Intermediate-AA142)

To a solution of Intermediate-AA142-6 (1.7 g, 4.85 mmol) in methanol (20mL), was added 10% palladium on charcoal (0.8 g). After stirring underhydrogen gas at atmospheric pressure for 2 h at RT, the reaction mixturewas filtered through celite-bed and washed with methanol. The filtratewas concentrated under reduced pressure. The residue was purified bytrituration with diethyl ether to afford Intermediate-AA142 (1.3 g,83.63%). MS (ES): m/z 321.19 [M+H]⁺

tert-butyl (1-(6-aminopyridin-2-yl)-5-oxopyrrolidin-3-yl)carbamate(Intermediate-AA143)

Step-1 synthesis of tert-butyl(1-(6-nitropyridin-2-yl)-5-oxopyrrolidin-3-yl)carbamate (IntermediateAA143-2)

To a solution of Intermediate AA51-1 (4 g, 25.31 mmol) and IntermediateAA143-1 (6.0 g, 30.37 mmol, 1.2 eq) in DMF (40 mL) was added potassiumphosphate tribasic (16.0 g, 75.93 mmol, 3.0 eq). After degassing underN2 stream for 15 min. Brett Phos (1.3 g, 2.53 mmol, 0.1 eq) and BrettPhos Pd G3 (1.8 g, 2.02 mmol, 0.08 eq) were added. After stirring at110° C. and for 1 h, the reaction mixture was cooled to RT, dilutedwater (200 mL) and extracted with ethyl acetate (3×70 mL). The combinedorganic extracts were washed with brine (200 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography eluting with 20-25% ethyl acetategradient in hexane to afford Intermediate-AA143-2 (6.0 g, 73.78%) as abrown solid. MS (ES): m/z=323.1 [M+H]⁺

Step-2 synthesis of tert-butyl(1-(6-aminopyridin-2-yl)-5-oxopyrrolidin-3-yl)carbamate(Intermediate-AA143)

To a solution of Intermediate-AA143-2 (2.0 g, 6.21 mmol) in methanol (20mL), was added 10% palladium on charcoal (1.0 g). After stirring underhydrogen gas at atmospheric pressure for 4 h at RT, the reaction mixturewas filtered through celite-bed and washed with methanol. The filtratewas concentrated under reduced pressure to afford Intermediate-AA143which was used in the next step without further purification. (1.9 g,quantitative). MS (ES): m/z 293.1 [M+H]⁺.

Synthesis of1-(6-chloro-3-morpholinopyridin-2-yl)-N,N-dimethylmethanamine(Intermediate-AA144)

Step-1 synthesis of 6-chloro-3-morpholinopicolinaldehyde (IntermediateAA144-1)

To a solution of Intermediate-AA135-1 (7.5 g 31.77 mmol) in THF (25 mL)at −78° C. was added to the solution of n-butyllithium (19 mL, 1.59mmol, 1.5 eq) in diethyl ether (35 mL). After stirring at −78° C. for 30min, 1-methylpiperidin-4-one (3.6 g 31.77 mmol) was added. Afterstirring for 45 min at −78° C., the reaction mixture was diluted withsodium bicarbonate solution (200 mL) and extracted with ethyl acetate(3×150 mL). The combined organic extracts were washed with brine (200mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by trituration with diethyl ether toobtain Intermediate AA144-1 (3 g, 34.91%) MS (ES) m/z 227.66 (M+H)⁺.

Step-2 Synthesis of1-(6-chloro-3-morpholinopyridin-2-yl)-N,N-dimethylmethanamine(Intermediate-AA144)

To a solution of Intermediate-AA144-1 (1 g) in methanol (10 mL) withacetic acid (0.1 mL) at 0° C. was added NaCN(BH3) (0.5 g, 4 eq). Afterstirring for 2 h, the reaction was diluted with water (90 mL) andextracted with ethyl acetate (3×50 mL). The combined organic extractswere washed with brine (100 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to afford Intermediate AA144 (600 mg, 53%). MS (ES):m/z=256.3 (M+H)+.

Synthesis of 5-cyclopentyl-6-((dimethylamino)methyl)pyridin-2-amine(Intermediate AA145)

Step-1 Synthesis of methyl 6-amino-3-bromopicolinate(Intermediate-AA145-2)

To a solution of Intermediate-AA145-1 (500 g, 3289.4 mmol) inacetonitrile (12.5 L) was portion wise added N-bromo succinimide (644 g,3618.4 mmol, 1.1 eq) at RT over 30 min. After stirring at RT for 30 min,the reaction mixture was quenched with 10% Na₂S₂O₃ solution in water(3.0 L) and the reaction mixture was evaporated to remove ACN. Theresidue was diluted with 10% Na₂S₂O₃ solution in water (20 L) andextracted with 50% ethyl acetate in hexanes (10 L×5). The combinedorganic layer was dried over sodium sulfate and concentrated underreduced pressure. The crude material was triturated with 25% ethylacetate in hexanes to afford Intermediate-AA145. MS (ES): m/z 231-233[M+2]⁺, ¹H NMR (400 MHz, CDCL3): δ 7.66 (d, 1H), 6.53 (d, 1H), 4.68 (S,2H), 3.98 (s, 3H). The other region isomer (methyl6-amino-5-bromopicolinate) also formed and it is separated via silicapurification. Desired regioisomer confirm by ¹H NMR and NOE analysis.

Step-2 Synthesis of methyl3-bromo-6-(bis(tert-butoxycarbonyl)amino)picolinate(Intermediate-AA145-3)

To a solution of Intermediate-AA145-2 (1100 g, 4782.6 mmol) in THF (20L) were added DMAP (116.7 g, 956.5 mmol, 0.2 eq) and Boc anhydride (2502g, 11478.2 mmol, 2.4 eq). After stirring at 75° C. for 1.5 h, thesolvent was evaporated and then residue diluted in brine solution andextracted by ethyl acetate (2×10 L). The combined organic layer wasdried over sodium sulfate and concentrated under vacuum. The residue waspurified by Colum chromatography eluting with 5% ethyl acetate inhexane. The desired material was further purified by trituration withhexanes (4 L) to afford Intermediate-AA145-3 (1700 g, 82.79%) as whitesolid. MS (ES): m/z 431-433 [M+2]⁺. ¹H NMR (400 MHz, DMSO): δ 8.32 (d,1H), 7.61 (d, 1H), 3.90 (s, 3H), 1.40 (s, 18H).

Step-3 Synthesis of methyl6-(bis(tert-butoxycarbonyl)amino)-3-(furan-3-yl)picolinateIntermediate-AA145-4

To a solution of the Intermediate-AA145-3 (730 g, 1693.7 mmol) and furanboronic acid 3 (379 g, 3387.4 mmol, 2 eq) in 1-4 dioxane (5.85 L) andwater (1.46 L) was added potassium phosphate tribasic (Sigma, 1078.3 g,5086.2 mmol, 3.0 eq). After degassing with flow of nitrogen for 20 min,bis(triphenylphosphine)palladium(II) dichloride (59.5 g, 84.8 mmol, 0.05eq) was added (Note: exothermicity was observe). After stirring at 120°C. for 15 min, the reaction was cooled to RT and the water layer wasseparated from reaction mixture. The organic layer was filtered throughcelite bed and concentrated under reduced pressure. The residue waspurified by silica gel chromatography eluting with 6 to 10% ethylacetate/hexanes. The collected material was triturated with n-pentane toafford Intermediate-AA145-4 as a cream colored solid. MS (ES): m/z 418[M+H]⁺ ¹H NMR (400 MHz, DMSO): δ 8.12 (d, 1H), 8.00 (d, 1H), 7.81 (s,1H), 7.61 (s, 1H), 6.70 (S, 1H), 3.83 (S, 3H), 1.41 (s, 18H).

Step-4 Synthesis of methyl6-(bis(tert-butoxycarbonyl)amino)-3-(furan-3-yl)picolinateIntermediate-AA145-5

To a solution of Intermediate-AA145-4 (191 g, 456.9 mmol) in methanol(1140 mL) and THF (955 mL) were added with ammonium formate (115.1 g,182.5 mmol, 4.0 eq), acetic acid (133.7 mL, 0.7V) and 20% WET palladiumhydroxide on carbon (133.7 g, 1:0.7 W/W). After stirring under anatmosphere of hydrogen gas for 24 h at RT, the reaction mixture wascombined with 6 other batches on the same scale prepared by an identicalmethod. The reaction mixture was then filtered through Celite bed, andthe filtrate was concentrated under reduced pressure. The residue wasneutralized with sat. NaHCO₃(10 L) solution and extracted by DCM (10L×3)to afford Intermediate-AA145-5 (1251 g, and 92.6%). MS (ES): m/z 423[M+1]⁺ ¹H NMR (400 MHz, DMSO): δ 8.01 (d, 1H), 7.58 (d, 1H), 3.99 (t,2H), 3.87 (S, 3H), 3.71 (m, 2H), 3.60 (m, 1H), 2.31 (m, 1H) 1.91 (d,1H), 1.4 (S, 18H).

Step-5 Synthesis of compound tert-butyl(6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate(Intermediate-AA145-6)

To a solution of Intermediate-AA145-5 (250 g, 592.4 mmol) in ethanol(2500 mL) was treated portion wise with sodium borohydride (135 g, 355.4mmol, 6 eq). After stirring at 60° C. for 2 h, the reaction wasevaporated under reduced pressure, diluted with water (10 L), andextracted by DCM (4×10 L). The combined organic layer was washed withbrine (10 L), passed through a Na₂SO₄, and concentrated under reducedpressure to afford Intermediate-AA145-6. The product was combined with 4other batches on the same scale prepared by an identical method. (640 g,73.49%), as colorless gummy liquid which turned into white solid at RTafter 2 days. MS (ES): m/z 295.0 [M+1]⁺ ¹H NMR (400 MHz, DMSO): δ 7.81(d, 1H), 7.67 (d, 1H), 7.2 (d, 1H), 5.22 (d, 1H), 4.55 (t, 1H), 3.99 (s,3H), 3.77 (m, 3H), 3.55 (m, 2H), 2.28 (d, 2H), 1.87 (d, 1H), 1.41 (s,9H)

Step-6, 7 Synthesis of tert-butyl(6-((dimethylamino)methyl)-5-(THF-3-yl)pyridin-2-yl)carbamate(Intermediate-AA145-7)

To a solution of Intermediate-AA145-6 (440 g, 149.6 mmol) in DCM (6.5 L)was added dropwise DIPEA (581.4 g, 448.9 mmol, 3.0 eq) at 0° C. Afterstirring for 20 min, mesyl chloride (257.04 g, 2244 mmol, 1.5 eq) wasadded dropwise at 0° C. After stirring at 0° C. to RT for 2 h, thereaction mixture was quenched with Water (1 L) and extracted by DCM (3×2L). The combined organic layer was washed with brine (10 L), passedthrough a Na₂SO₄, and concentrated under reduced pressure to affordmesylated intermediate. This product was combined with 1 other batcheson the 200 g scale prepared by an identical method. (700 g-crude,86.44%), as light yellow liquid. MS (ES): m/z 373.35 [M+1]⁺. To asolution of mesylated product above (350 g, 940.0 mmol) in MeCN (3.5 L)was added dropwise DIPEA (529.23 g, 423.0 mmol, 4.5 eq) followed bydimethylamine hydrochloride (152.41 g, 1880.0 mmol, 2.0 eq) at RT. Afterstirring at 90° C. for 3 h, the reaction mixture was evaporated toremove ACN. The residue was quenched in Water (1500 mL) and extracted byDCM (3×3 L). The combined organic layer was washed with brine (10 L),dried with Na₂SO₄, and concentrated under reduced pressure to affordIntermediate-AA145-7. The product was combined with 1 other batches onthe same scale prepared by an identical method. (700 g, quantitativeyield), as brown semisolid. MS (ES): m/z 322.39 [M+1]⁺, ¹H NMR (400 MHz,DMSO): δ 9.61 (S, 1H), 7.67 (S, 2H),3.96-3.94 (t, 2H, J=7.6), 3.78-3.77(d, 2H, J=4 HZ), 3.57 (S, 1H), 3.54 (s, 1H), 2.26-2.25 (t, 1H), 2.1 (S,6H), 1.86 (S, 1H), 1.45 (s, 9H)

Step-8 Synthesis of compound5-cyclopentyl-6-((dimethylamino)methyl)pyridin-2-amine(Intermediate-AA145)

To a solution of Intermediate-AA145-7 (700 g, 2180.7 mmol) in DCM (5.0L) was added TFA (2.1 L, 3v) at 0° C. After stirring at 70° C. for 2 h,the reaction mixture was evaporated. The residue was diluted in Water (2L) and extracted with heptane. The heptane layer was discarded. Theaqueous layer was neutralized with 10% NaOH solution and extracted by15% MeOH in DCM (4×3 L). The combined organic layer was dried oversodium sulfate and concentrated under reduced pressure. The residue wastriturated with 20% ethyl acetate in hexanes and then diethyl ether toafford Intermediate-AA145 as light brown solid. (330 g, 68.47%). MS(ES): m/z 222.30 [M+1]⁺, 1H NMR (400 MHz, DMSO-d6) δ 7.33 (d, J=8.4 Hz,1H), 6.36 (d, J=8.5 Hz, 1H), 5.71 (s, 1H), 3.96-3.85 (m, 1H), 3.72 (dq,J=31.0, 7.7 Hz, 1H), 3.46-3.34 (m, 1H), 3.35 (s, 1H), 3.30 (d, J=11.9Hz, 0H), 2.19 (td, J=7.8, 4.2 Hz, 0H), 2.14 (s, 3H), 1.79 (dq, J=12.2,8.0 Hz, 1H).

Synthesis of1-(2-(4-(6-aminopyridin-3-yl)morpholin-2-yl)propan-2-yl)azetidin-3-ol(Intermediate-AA146)

Step 1 Synthesis of1-((2-(4-benzylmorpholin-2-yl)propan-2-yl)amino)-3-chloropropan-2-ol(Intermediate AA146-1)

To a solution of Intermediate AA93-2 (5 g, 26.7 mmol, 1.0 eq) in IPA wasadded 2-(chloromethyl) oxirane (3.5 g, 26.7 mmol, 1.5 eq). Afterstirring at RT for 16 h, the reaction mixture was concentrated underreduced pressure. The residue was purified by column chromatography(3.5% methanol gradient in DCM) to afford Intermediate AA146-1 (0.4 g,6%), MS (ES): m/z=326 [M+H]⁺

Step 2 Synthesis of 1-(2-(4-benzylmorpholin-2-yl)propan-2-yl)azetidin-3-ol (Intermediate AA146-2)

To a solution of Intermediate AA146-1 (1.9 g, 5.5 mmol), in acetonitrilewas added TEA (1.2 mL, 8.2 mmol, 1.5 eq). After stirring at 80° C. for16 h, the reaction mixture was concentrated under reduced pressure. Theresidue was purified by column chromatography to afford the titlecompound (Intermediate AA146-2) (1.30 g, 77%). MS (ES): m/z=290 (M+H).

Step-3 synthesis of2-(4-(6-nitropyridin-3-yl)-1,4-oxazepan-6-yl)propan-2-ol (IntermediateAA146-3)

To a solution of Intermediate AA146-2 (2.5 g) in EtOH (15 mL) were added10% Pd/C (0.50 g) and (0.5 g) Pd(OH)₂. After stirring under H2 gas atatmospheric pressure for 16 h in autoclave, the reaction mixture wasfiltrate through celite bed. The organic layer was evaporated in vacuumto afford Intermediate AA146-3 (1.8 g, quantitative) which was used inthe next step without purification. MS (ES): m/z=200 [M+1]+

Step-4 synthesis of1-(2-(4-(6-nitropyridin-3-yl)morpholin-2-yl)propan-2-yl)azetidin-3-ol(Intermediate AA146-4)

To a solution of Intermediate AA146-3 (1.8 g, 9 mmol) in DMSO (15 mL)were added dropwise DIPEA (10 mL) and then dropwise5-fluoro-2-nitropyridine (1.9 g, 13 mmol, 1.5 eq). After stirring for 45min at 120° C., the reaction mixture was cooled at RT and diluted withethyl acetate (20 mL) and water (15 mL). The organic layer wascollected, and the aqueous phase was extracted with ethyl acetate (2×30mL). The combined organic extracts were washed with brine (10 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography (3.5% methanol gradient inDCM) to afford the title compound Intermediate AA146-4 (0.8 g, 27%), MS(ES): m/z=322[M+H]⁺

Step-5 synthesis of1-(2-(4-(6-aminopyridin-3-yl)morpholin-2-yl)propan-2-yl)azetidin-3-ol(Intermediate AA146)

To a solution of Intermediate AA146-4 (0.8 g) in MeOH (10 mL) wastreated with 10% Pd/c (0.150 g). After stirring at RT for 2 h with H2gas at atmospheric pressure, the reaction mixture was filtered throughcelite bed. The organic solution was evaporated in vacuum to affordIntermediate AA146 (0.7 g, quantitative) which was used in the next stepwithout purification. MS (ES): m/z=292[M+1]⁺

Synthesis of 1-(6-bromopyridin-2-yl)-N,N-dimethylmethanamine(Intermediate-AA147)

Step-1 Synthesis of 1-(6-bromopyridin-2-yl)-N,N-dimethylmethanamine(Intermediate AA147)

To a solution of Intermediate AA147-1 (0.700 g, 0.3 mmol) and sodiumtriacetoxy borohydride (8 g) in DCE (6 mL) was added glacial acetic acid(0.8 mL). After degassing using nitrogen gas for 20 min, dimethylamine(10 mL) was added. After stirring overnight, the reaction mixture wasdiluted with water and extracted with ethyl acetate. The combinedorganic layer was washed with brine solution, dried over sodium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel eluting with 2-4% MeOH/DCM to afford Intermediate AA147(0.189 g, 25.43%), LCMS: 95%, MS (ES): m/z 215.2 [M+H]⁺

Synthesis of3R,4R)-1-(6-chloro-2-((dimethylamino)methyl)pyridin-3-yl)-4-fluoropiperidin-3-ol(Intermediate-AA148)

Step-1 Synthesis of 3R,4R)-4-fluoropiperidin-3-ol (Intermediate AA148-2)

To a solution of Intermediate AA148-1(2.2 g, 10.04 mmol) in DCM (20 mL)was added dropwise 4 M HCl in dioxane (20 mL) at RT. After stirring atRT for 2 h, the reaction mixture was concentrated under reducedpressure. The residue was purified by trituration with diethyl ether toafford Intermediate AA148-2 (1.7 g, quantitative) which was used in thenext step without purification, MS (ES): m/z=120.2 [M+H]⁺

Step-2 Synthesis of6-chloro-3-((3R,4R)-4-fluoro-3-hydroxypiperidin-1-yl)picolinaldehyde(Intermediate AA148-3)

To a solution of 6-chloro-3-fluoropicolinaldehyde (1.7 g, 10.69 mmol)and Intermediate AA148-2 (2.5 g, 21.38 mmol, 2.0 eq) in DMF (20 mL) wasadded dry potassium carbonate (7.3 g, 53.45 mmol, 5.0 eq). Afterstirring for 1 h at 100° C., the reaction mixture was cooled at RT anddiluted with water (150 mL). The organic layer was collected, and theaqueous phase was extracted with ethyl acetate (3×50 mL). The combinedorganic extracts were washed with brine (100 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography (20% ethyl acetate gradient in hexane)to afford Intermediate AA148-3 (1.3 g, 47.16%), MS (ES): m/z=259.3[M+H]⁺

Step-3 Synthesis of3R,4R)-1-(6-chloro-2-((dimethylamino)methyl)pyridin-3-yl)-4-fluoropiperidin-3-ol(Intermediate AA148)

To a solution of Intermediate AA148-3 (1.3 g, 5.03 mmol) in methanol:DCM (10 mL:10 mL) was added dimethylamine solution (2M in THF) (3.7 mL,7.54 mmol, 1.5 eq). After stirring for 30 min at RT, acetic acid (0.3mL) and sodium cyanoborohydride (0.63 g, 10.06 mmol, 2.0 eq) were added.After stirring for 30 min at RT, the reaction mixture was diluted withsodium bicarbonate solution (100 mL) and extracted with DCM (3×50 mL).The combined organic extracts were washed with brine (100 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography (0.5% methanol gradient inDCM) to afford Intermediate AA148 (0.9 g, 62.23%), MS (ES): m/z=288.2[M+H]⁺

Synthesis of tert-butyl((6-amino-3-(THF-3-yl)pyridin-2-yl)methyl)carbamate (Intermediate-AA149)

Step-1 Synthesis of methyl 3-bromo-6-(cyclopropanecarboxamido)picolinate(Intermediate AA149-1)

To a solution of Intermediate AA145-2 (4.0 g, 17.46 mmol) in DCM (40 mL)at 0° C. were added triethylamine (7.3 mL, 52.38 mmol, 3.0 eq) andcyclopropanecarbonyl chloride (7.2 g, 69.84 mmol, 4.0 eq). Afterstirring at RT for 2 h, the reaction mixture was diluted with water (150mL) and extracted with DCM (3×70 mL). The combined organic extracts werewashed with brine (200 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography (18% ethyl acetate gradient in hexane) to affordIntermediate AA149-1 (4.8 g, 92.69%) MS (ES): m/z=299.2 [M+H]⁺

Step-2 Synthesis of methyl6-(cyclopropanecarboxamido)-3-(furan-3-yl)picolinate (IntermediateAA149-2)

To a solution of Intermediate AA149-1 (4.0 g, 13.37 mmol) in dioxane (35mL) and water (6 mL) were added furan-3-ylboronic acid (1.8 g, 16.04mmol, 1.2 eq) and potassium phosphate tribasic (8.5 g, 40.11 mmol, 3.0eq). After degassing with N2 for 15 min,bis(triphenylphosphine)palladium(II) dichloride (0.463 g, 0.66 mmol,0.05 eq) was added. After stirring at 110° C. for 2 h, the reactionmixture was cooled to RT, diluted water (150 mL) and extracted withethyl acetate (3×100 mL). The combined organic extracts were washed withbrine (200 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with 20% ethyl acetate gradient in hexane to afford IntermediateAA149-2 (3.5 g, 91.42%), MS (ES): m/z 287.2 [M+H]⁺

Step-3 Synthesis of methyl6-(cyclopropanecarboxamido)-3-(THF-3-yl)picolinate (IntermediateAA149-3)

In autoclave, a solution of Intermediate AA149-2 (3.5 g, 12.23 mmol) inmethanol (35 mL) were added ammonium formate (1.5 g, 24.46 mmol, 2.0eq), acetic acid (3 mL). and palladium hydroxide on carbon (20%) (2.2g). After stirring at 20 psi hydrogen atmosphere for 16 h, the reactionmixture was filtered through celite-bed and washed with methanol. Thefiltrate was concentrated under reduced pressure. The residue waspurified by column chromatography eluting with 25% ethyl acetategradient in hexane to afford Intermediate AA149-3 (2.5 g, 70.44%). MS(ES): m/z 291.2 [M+H]⁺

Step-4 Synthesis ofN-(6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA149-4)

To a cooled solution of Intermediate AA149-3 (2.5 g, 8.62 mmol) inethanol at 0° C. (25 mL) was added portion wise sodium borohydride (1.3g, 34.48 mmol, 4.0 eq). Reaction mixture stirred at RT for 1 h, thereaction mixture was concentrated under reduced pressure, diluted withwater (70 mL), and extracted with DCM (3×40 mL). The combined organicextracts were washed with brine (80 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 30% ethyl acetate gradient in hexaneto afford Intermediate AA149-4 (1.4 g, 61.98%), MS (ES): m/z 263.2[M+H]⁺

Step-5,6 Synthesis ofN-(6-(azidomethyl)-5-(THF-3-yl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA149-5)

To a solution of Intermediate AA149-4 (1.3 g, 4.96 mmol) in DCM (15 mL)with triethylamine (1.7 mL, 11.70 mmol, 2.36 eq) at 0° C. was addedmethane sulfonyl chloride (0.7 mL, 9.92 mmol, 2.0 eq) dropwise. Afterstirring at 0° C. for 1 h, the reaction mixture was diluted with water(80 mL), washed with sodium bicarbonate solution, and extracted with DCM(3×40 mL). The combined organic extracts were washed with brine (80 mL),dried over Na₂SO₄, filtered, and concentrated under reduced pressure (2g). The residue (2.0 g, 5.88 mmol) was added a solution of sodium azide(0.764 g, 11.76 mmol, 2.0 eq) and 18-Crown-6 (0.062 g, 0.23 mmol, 0.04eq) in acetonitrile (20 mL). After stirring at RT for 2 h, the reactionmixture was filtered through celite-bed. The filtrate was concentratedunder reduced pressure to afford Intermediate AA149-5 (0.8 g, 56.18%),MS (ES): m/z 288.1 [M+H]⁺

Step-7, 8 Synthesis of tert-butyl((6-(cyclopropanecarboxamido)-3-(THF-3-yl)pyridin-2-yl)methyl)carbamate(Intermediate AA149-6)

To a solution of Intermediate AA149-5 (0.8 g, 2.78 mmol) in ethanol (10mL) was added. palladium on charcoal (0.4 g). After stirring underhydrogen gas at atmospheric pressure for 4 h at RT, the reaction mixturewas filtered through celite-bed and washed with methanol. The filtratewas concentrated under reduced pressure (0.68 g). The residue (0.68 g,2.60 mmol) was dissolve in DCM (6 mL) with trimethylamine (1.8 mL, 7.8mmol, 3.0 eq). The reaction mixture was cooled to 0° C. anddi-tert-butyl dicarbonate (0.68 g, 7.8 mmol, 3.0 eq) was added. Afterstirring at RT for 30 min, the reaction mixture was filtered throughcelite-bed. The filtrate was concentrated under reduced pressure toafford Intermediate AA149-6 (0.7 g, 69.56%), MS (ES): m/z 362.2 [M+H]⁺

Step 9. tert-butyl ((6-amino-3-(THF-3-yl)pyridin-2-yl)methyl)carbamate(Intermediate AA149)

To a solution of Intermediate AA149-6 (0.7 g, 1.93 mmol) in methanol (7mL) and water (2 mL) was added sodium hydroxide (0.9 g, 23.16 mmol, 12.0eq). After stirring at 40° C. for 10 h, the reaction mixture was cooledto RT, concentrated under reduced pressure, diluted water (70 mL) andextracted with ethyl acetate (3×40 mL). The combined organic extractswere washed with brine (60 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford Intermediate AA149 (0.5 g,88.00%), MS (ES): m/z 294.2 [M+H]⁺

Synthesis of4-(6-chloropyridin-3-yl)-N,N-dimethyltetrahydro-2H-pyran-4-amine(Intermediate-AA150)

Step-1 Synthesis of methyl 2-(6-chloropyridin-3-yl)acetate (IntermediateAA150-2)

To a solution of Intermediate AA150-1 (2.5 g, 14.61 mmol) in methanol(25 mL) was added concentrated sulfuric acid (1 mL) at RT. Afterstirring at RT for 1 h, the reaction mixture was neutralized with sodiumbicarbonate solution and extracted with ethyl acetate (3×60 mL). Thecombined organic extracts were washed with brine (100 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure to affordIntermediate AA150-2 (2.4 g, 88.74%) which was used in the next stepwithout purification. MS (ES): m/z=186.2 [M+H]⁺

Step-2 Synthesis of methyl4-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-4-carboxylate (IntermediateAA150-3)

To a cooled solution of Intermediate AA150-2 (2.4 g, 12.97 mmol) and1-bromo-2-(2-bromoethoxy)ethane (1.8 g, 7.78 mmol, 0.6 eq) in THF (80mL) at 0° C. was added dropwise lithium bis(trimethylsilyl)amide (1M inTHF) (9.5 mL) under N² atmosphere. After stirring for 2 h at RT, lithiumbis(trimethylsilyl)amide (9.5 mL) was added. After stirring for 16 h atRT, the reaction mixture was quenched with brine solution (80 mL) andextracted with ethyl acetate (3×50 mL). The combined organic solutionwas dried over Na₂SO₄, filtered, and concentrated under reduced pressureto afford Intermediate AA150-3 (2.4 g, 72.59%), which was used in nextstep without purification. MS (ES): m/z=256.2 [M+H]⁺

Step-3 Synthesis of4-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-4-carboxylic acid(Intermediate AA150-4)

To a solution of Intermediate AA150-3 (2.4 g, 9.41 mmol) in methanol (25mL) was added 6N NaOH solution (10 mL). After stirring at 70° C. for 2h, 4M HCl in dioxane was added. After stirring for 10 min, the reactionmixture was concentrated under reduced pressure. The residue waspurified by column chromatography (7% methanol gradient in DCM) toafford Intermediate AA150-4 (2.0 g, 88.17%) MS (ES): m/z=242.2 [M+H]⁺

Step-4 Synthesis of tert-butyl(4-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-4-yl)carbamate(Intermediate AA150-5)

To a solution of Intermediate AA150-4 (2.0 g, 8.29 mmol) with 4 amolecular sieve under N2 gas atmosphere in tert-Butyl alcohol (20 mL)were added diphenylphosphoryl azide (2.5 mL) and triethylamine (2.5 mL)dropwise to reaction mixture. After stirring at RT for 1 h then for 16 hat 70° C., the reaction mixture was filtered, and filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography (25% ethyl acetate gradient in hexane) to affordIntermediate AA150-5 (1.4 g, 54.08%) MS (ES): m/z=313.2 [M+H]⁺

Step-5 Synthesis of 4-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-4-amine(Intermediate AA150-6)

To a solution of Intermediate AA150-5 (1.4 g, 4.48 mmol, 1 eq) in DCM(20 mL) at 0° C. was dropwise added 4N hydrochloric acid in dioxane (15mL). After stirring at RT for 3 h., the reaction mixture was neutralizedwith sodium bicarbonate solution and extracted with ethyl acetate (3×50mL). The combined organic layer was dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford Intermediate AA150-6 (1.0g, 94.55%). MS (ES): m/z 213.07 [M+H]⁺

Step-6 Synthesis of4-(6-chloropyridin-3-yl)-N,N-dimethyltetrahydro-2H-pyran-4-amine(Intermediate AA150)

To a solution of Intermediate AA150-6 (1.0 g, 4.71 mmol) in methanol (10mL) added Formaldehyde (0.282 g, 9.42 mmol, 2.0 eq) and stirred reactionmixture for 30 min. Then added acetic acid (3.3 mL) and portion wisesodium cyanoborohydride (0.741 g, 11.77 mmol, 2.5 eq) at 0° C. Thereaction mixture stirred for 3 h at 60° C. After completion of reaction,the reaction mixture was concentrated under reduced pressure. Theresidue was purified by column chromatography (3.0% methanol gradient inDCM) Intermediate AA150 (0.9 g, 79.51%), MS (ES): m/z=241.3 [M+H]⁺

Synthesis of6-((dimethylamino)methyl)-5-(2-(methoxymethyl)morpholino)pyridin-2-amine(Intermediate AA151)

Step-1 Synthesis of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate(Intermediate AA151-2)

To a solution of the Intermediate AA125-1 (10 g, 38.6 mmol) in methanol(100 mL) at 0° C. was added NaBH4 (4 g, 115.8 mmol, 3 eq) portion wise.After stirring at RT for 3 h, the reaction was quenched with water (100mL) and extracted with ethyl acetate (3×40 mL). The combined organiclayer was washed with brine, passed through a hydrophobic filter, andevaporated in vacuum to afford Intermediate AA151-2 (8 g, 95.48%) whichwas used in the next step without purification MS (ES): m/z 218.1[M+H]⁺.

Step-2 Synthesis of tert-butyl 2-(methoxymethyl)morpholine-4-carboxylate(Intermediate-AA151-3)

A solution of Intermediate-AA151-2 (8 g, 36.6, 1 eq), in DMF (80 mL) wasadded NaH (2.93 g, 73.3 mmol, 2 eq) and MeI (4.1 g, 43.92 mmol, 1.2 eq).After stirring for 4 h, the reaction mixture was diluted with water (150mL) and extracted with ethyl acetate (3×100 mL). The combined organicextracts were wash with brine (150 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography to afford Intermediate-AA151-3) (7.5 g, 88.06%) MS (ES):m/z=232.29 [M+H]⁺

Step-3 Synthesis of 2-(methoxymethyl)morpholine (Intermediate-AA151-4)

To a solution of Intermediate AA151-3 (7.5 g) into DCM (75 mL) at 0° C.was added 4 M HCl in dioxane (32 mL). After stirring at RT for 1 h, thereaction mixture was neutralized using saturated sodium bicarbonatesolution and extracted with DCM to get pure title compound (IntermediateAA151-3) (4 g, 94.05%) MS (ES): m/z 132.6 (M+H)+.

Step-4 Synthesis of6-chloro-3-(2-(methoxymethyl)morpholino)picolinaldehyde(Intermediate-AA151-5)

To a solution of Intermediate-AA151-4 (7.5 g, 57.2 mmol) in DMF (75 mL)were added K₂CO₃ (23.7 g, 171.7 mmol, 3 eq) and6-chloro-3-fluoropicolinaldehyde (11.74 g, 74.36 mmol, 1.3 eq). Afterstirring at 100° C. for 4 h, the reaction mixture was quenched in water(100 mL) and extracted with ethyl acetate (100 mL×3). The organic layerwas combined and dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by column chromatography toafford Intermediate-AA151-5 (6 g, 38.21%). MS (ES): m/z 271.71 [M+H]⁺

Step-5 synthesis of1-(6-chloro-3-(2-(methoxymethyl)morpholino)pyridin-2-yl)-N,N-dimethylmethanamine(Intermediate-AA151-6)

To a solution of Intermediate Intermediate-AA151-4 (5 g, 18.4 mmol) inmethanol (50 mL) at 0° C. were added acetic acid (5 mL) and dimethylamine (1.3 g,27.6 mmol,1.5 eq). After stirring at RT for 45 min,NaCN(BH3) (73.6 mmol, 4 eq) was added. After stirring for 2 h, thereaction was diluted with water (90 mL) and extracted with ethyl acetate(3×50 mL). The combined organic extracts were washed with brine (100mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica gel chromatography toafford Intermediate AA151-6 (3.5 g, 61%). MS (ES): m/z=300.8 (M+H)+.

Step-6 synthesis ofN-(6-((dimethylamino)methyl)-5-(2-(methoxymethyl)morpholino)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA151-7)

To a solution of Intermediate AA151-6 (1 g, 3.3 mmol) and1-cyclopropanecarboxamide (0.5 g, 6.0 mmol, 1.8 eq) in 1,4-dioxane (10mL) was added potassium carbonate (1.3 g, 9.9 mmol, 3.0 eq). Afterdegassing under N2 stream for 15 min, Xantphos (0.382 g, 1.59 mmol, 0.66eq) and Pd₂(dba)₃ (0.274 g, 0.3 mmol, 0.1 eq) added. After stirring at110° C. for 1 h, the reaction mixture was cooled to RT, diluted water(70 mL) and extracted with ethyl acetate (2×50 mL). The combined organicextracts were washed with brine (80 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography to afford Intermediate AA1151-7 (0.800 g, 68%) MS(ES): m/z=349.45 [M+H]⁺

Step-7 synthesis of6-((dimethylamino)methyl)-5-(2-(methoxymethyl)morpholino)pyridin-2-amine(Intermediate AA151)

To a solution of Intermediate AA151-7 (0.800 g, 2.2 mmol) inmethanol:water (20 mL:5 mL) was added sodium hydroxide (0.91 g, 22 mmol,10 eq). After stirring at RT for 16 h, the reaction mixture wasconcentrated under reduced pressure. The residue was diluted with water(50 mL) at 10° C. and neutralized with 1N hydrochloric acid to pH-6-6.5.Product was extracted with DCM (3×40 mL). The combined organic layerswere washed with brine solution, dried over sodium sulfate, andconcentrated under reduced pressure to afford Intermediate AA151 (0.4 g,62%). MS (ES): m/z 281.37 [M+H]⁺

Synthesis of1-(6-aminopyridin-3-yl)-3-(2-(dimethylamino)propan-2-yl)piperidin-3-ol(Intermediate-AA152)

Step-1 Synthesis of1-benzyl-3-((trimethylsilyl)oxy)piperidine-3-carbonitrile (IntermediateAA152-2)

To a solution of Intermediate AA152-1 (15.0 g, 79.36 mmol) in dry DCMwere added trimethylsilyl cyanide (12.95 mL, 103.16 mmol, 1.3 eq) andzinc iodide (2.5 g, 7.93 mmol, 0.1 eq) (25 mL). After stirring at refluxfor 2 h, the reaction mixture was cooled to RT, diluted with water (200mL), and extracted with ethyl acetate (3×120 mL). The combined organicextracts were washed with brine (200 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography (10-15% ethyl acetate gradient in hexane) toafford Intermediate AA152-2 (14.4 g, 62.98%) MS (ES): m/z=289.1 [M+H]⁺

Step-2 Synthesis of 3-(2-aminopropan-2-yl)-1-benzylpiperidin-3-ol(Intermediate AA152-3)

After stirring a solution of cerium (III) chloride (17.11 g, 69.44 mmol,2.0 eq) in THF (100 mL) at 45° C. for 2 h, Intermediate AA152-2 (10.0 g,34.72 mmol) and methyllithium solution (1.6M in diethyl ether) (54 mL,86.8 mmol, 2.5 eq) were added dropwise at 0° C. After stirring for 30min at RT, the reaction mixture was quenched with cold water (500 mL)and extracted with 10% methanol in DCM (3×200 mL). The combined organicextracts were washed with brine (400 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography (2% methanol gradient in DCM) to affordIntermediate AA152-3 (2.0 g, 23.23%) MS (ES): m/z=249.1 [M+H]⁺

Step-3 Synthesis of1-benzyl-3-(2-(dimethylamino)propan-2-yl)piperidin-3-ol (IntermediateAA152-4)

To a solution of Intermediate AA152-3 (1.2 g, 4.83 mmol) in methanol (15mL) were add formaldehyde (1.2 g) and trimethylamine (1.0 mL, 7.24 mmol,1.5 eq). After stirring at RT for 1 h, sodium cyanoborohydride (0.6 g,9.66 mmol, 2.0 eq) was added. After stirring at RT for 16 h, thereaction mixture was quenched with water (100 mL) and extracted withethyl acetate (3×40 mL). The combined organic extracts were washed withbrine (90 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatography (3%methanol gradient in DCM) to afford Intermediate AA152-4 (1.0 g, 74.88%)MS (ES): m/z=277.2[M+H]⁺

Step-4 Synthesis of 3-(2-(dimethylamino)propan-2-yl)piperidin-3-ol(Intermediate AA152-5)

To a solution of Intermediate AA152-4 (1.1 g, 3.97 mmol) in methanol (15mL) and concentrated HCl (0.5 mL) was added palladium hydroxide oncarbon (20%, 0.5 g) under N2 atmosphere. After stirring under hydrogengas at atmospheric pressure for 2 h at RT, the reaction mixture wasfiltered through celite-bed and washed with methanol. The filtrate wasconcentrated under reduced pressure to afford Intermediate AA152-5 (0.8g, quantitative yield) MS (ES): m/z=187.1 [M+H]⁺

Step-5 Synthesis of3-(2-(dimethylamino)propan-2-yl)-1-(6-nitropyridin-3-yl)piperidin-3-ol(Intermediate AA152-6)

To a solution of Intermediate AA30-1 (0.5 g, 3.52 mmol) and IntermediateAA152-5 (0.98 g, 5.28 mmol, 1.5 eq) in DMSO (5 mL) was added N,N-diisopropylethylamine (2.4 mL, 14.08 mmol, 4.0 eq). After stirring at110° C. for 4 h, the reaction mixture was diluted with water (80 mL) andextracted with DCM (3×40 mL). The combined organic extracts were washedwith brine (90 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatography (2%methanol gradient in DCM) to afford Intermediate AA152-6 (0.350 g,32.25%) MS (ES): m/z=309.2 [M+H]⁺

Step 6 Synthesis of1-(6-aminopyridin-3-yl)-3-(2-(dimethylamino)propan-2-yl)piperidin-3-ol(Intermediate AA152)

To a solution of Intermediate AA152-6 (0.350 g, 1.13 mmol) in methanol(5 mL) was added palladium on charcoal (0.170 g). After stirring underhydrogen gas at atmospheric pressure for 4 h at RT, the reaction mixturewas filtered through celite-bed and washed with methanol. The filtratewas concentrated under reduced pressure to afford Intermediate AA152(0.240 g, 75.96%) which was used in next step without purification. MS(ES): m/z 279.2 [M+H]⁺

Synthesis of6-((3,3-difluoropyrrolidin-1-yl)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA153)

6-((3,3-difluoropyrrolidin-1-yl)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate AA153) was prepared from tert-butyl(6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate (IntermediateAA145-6) and 3,3-difluoropyrrolidine in a similar fashion to thatprocedure of step-6, step-7 and step-8 described in synthesis of5-cyclopentyl-6-((dimethylamino)methyl)pyridin-2-amine (IntermediateAA145) (0.8 g, 90.22%). m/z 284.15 [M+H]⁺

Synthesis of4-(6-chloro-2-((dimethylamino)methyl)pyridin-3-yl)tetrahydro-2H-pyran-4-ol(Intermediate-AA154)

Step-1 Synthesis of methyl 3-bromo-6-chloropicolinate (IntermediateAA154-2)

To a solution of Intermediate AA154-1 (8.0 g, 34.18 mmol) in DMF (80 mL)at 0° C. with added potassium carbonate (18.86 g, 136.72 mmol, 4.0 eq)was added methyl iodide (8.5 mL, 136.72 mmol, 4.0 eq) dropwise. Afterstirring for 2 h at RT, the reaction mixture was diluted with ice coldwater (400 mL) and extracted with ethyl acetate (3×150 mL). The combinedorganic extracts were washed with brine (2×200 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography (35% ethyl acetate gradient in hexane)to afford Intermediate AA154-2 (3.5 g, 41.30%) MS (ES): m/z=250.9 [M+H]⁺

Step-2 Synthesis of 3-bromo-6-chloropyridin-2-yl)methanol (IntermediateAA154-3)

To a solution of Intermediate AA154-2 (8.0 g, 32.00 mmol) in ethanol (80mL) at 0° C. was added sodium borohydride (4.8 g, 128 mmol, 4.0 eq)portion wise. After completion of reaction, the reaction mixture wasquenched with water (300 mL) and extracted with DCM (3×100 mL). Thecombined organic extracts were washed with brine (2×100 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography (0.7% methanol gradient in DCM) toafford Intermediate AA154-3 (3.5 g, 49.26%) MS (ES): m/z=222.9[M+H]⁺

Step-3 Synthesis of3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloropyridine(Intermediate AA154-4)

To a solution of Intermediate AA154-3 (7.0 g, 31.53 mmol) in DCM (70 mL)were added DMAP (0.769 g, 6.30 mmol, 0.2 eq), imidazole (2.7 g, 40.67mmol, 1.29 eq) and tert-butyldimethylsilyl chloride (5.6 g, 37.83 mmol,1.2 eq) portion wise. After stirring at RT for 16 h, the reactionmixture was diluted with water (400 mL) and extracted with DCM (3×150mL). The combined organic extracts were washed with brine (150 mL),dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by column chromatography (20% ethyl acetategradient in hexane) to afford Intermediate AA154-4 (4.0 g, 37.75%) MS(ES): m/z=336.2 [M+H]⁺

Step-4 Synthesis of4-(2-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloropyridin-3-yl)tetrahydro-2H-pyran-4-ol(Intermediate AA154-5)

To a solution of Intermediate AA154-4 (8.0 g, 23.88 mmol) in THF (80 mL)at −78° C. was added n-butyllithium (2.5M in hexane) (11.5 mL, 28.65mmol, 1.2 eq). After stirring for 30 min, tetrahydro-4H-pyran-4-one (4.7g, 47.76 mmol, 2.0 eq) was added. After stirring at RT for 30 min, thereaction mixture was diluted with water (500 mL) and extracted with DCM(3×200 mL). The combined organic extracts were washed with brine (300mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography (20% ethylacetate gradient in hexane) to afford Intermediate AA154-5 (5.0 g,58.79%) MS (ES): m/z=358.2 [M+H]⁺

Step-5 Synthesis of4-(6-chloro-2-(hydroxymethyl)pyridin-3-yl)tetrahydro-2H-pyran-4-ol(Intermediate AA154-6)

To a solution of Intermediate AA154-5 (5.0 g, 13.96 mmol) in THF (50 mL)at 0° C. was added dropwise tetra-n-butylammonium fluoride (20 mL, 69.8mmol, 5.0 eq). After stirring at RT for 1 h, the reaction mixture wasdiluted with water (150 mL) and extracted with ethyl acetate (3×40 mL).The combined organic extracts were washed with brine (200 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography (40% ethyl acetategradient in hexane) to afford Intermediate AA154-6 (2.5 g, 73.44%) MS(ES): m/z=244.07 [M+H]⁺

Step-6, 7 Synthesis of4-(6-chloro-2-((dimethylamino)methyl)pyridin-3-yl)tetrahydro-2H-pyran-4-ol(Intermediate AA154)

To a solution of Intermediate AA154-6 (2.5 g, 10.28 mmol) in DCM (25 mL)at 0° C. were added triethylamine (4.3 mL, 30.84 mmol, 3.0 eq) andmethane sulfonyl chloride (1.6 mL, 20.56 mmol, 2.0 eq). After completionof reaction, the reaction mixture was diluted with water (50 mL) andextracted with ethyl acetate (3×30 mL). The combined organic extractswere washed with brine (40 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure (6 g). To a solution of mesylateintermediate (6.0 g, 18.69 mmol) in acetonitrile (30 mL) with potassiumcarbonate (10.3 g, 74.76 mmol, 4.0 eq) was added dimethylaminehydrochloride (15 g, 186.9 mmol, 10 eq) portion wise. After stirring at100° C. for 2 h, the reaction mixture was diluted with water (200 mL)and extracted with DCM (3×100 mL). The combined organic extracts werewashed with brine (200 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography (25% ethyl acetate gradient in hexane) to affordIntermediate AA154 (1.0 g, 36.00%) MS (ES): m/z=271.2 [M+H]⁺

Synthesis of 6-(morpholinomethyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA155)

6-(morpholinomethyl)-5-(THF-3-yl)pyridin-2-amine (Intermediate-AA155)was prepared from tert-butyl(6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate (IntermediateAA145-6) and morpholine in a similar fashion to that procedure ofstep-6, step-7 and step-8 described in synthesis of5-cyclopentyl-6-((dimethylamino)methyl)pyridin-2-amine (IntermediateAA145) (quantitative %). m/z 264.1 [M+H]⁺

Synthesis of 6-(2-(dimethylamino)ethyl)-5-morpholinopyridin-2-amine(Intermediate-AA156)

Step-1 Synthesis of 5,6-dibromopyridin-2-amine (Intermediate AA156-2)

To a cooled solution of Intermediate AA156-1 (10.0 g, 57.80 mmol) in DMF(50 mL) was added slowly N-Bromosuccinimide (11.3 g, 63.58 mmol, 1.1eq). After stirring at RT for 16 h, the reaction mixture was dilutedwith water (300 mL) and extracted with ethyl acetate (3×90 mL). Thecombined organic extracts were washed with brine (250 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography eluting with 5-8% elution ethylacetate in hexane to afford the title compound Intermediate AA156-2 (7.0g, 48.08%) MS (ES): m/z=251.8 [M+H]⁺

Step-2 Synthesis of 5-bromo-6-((trimethylsilyl)ethynyl)pyridin-2-amine(Intermediate AA156-3)

To a solution of Intermediate AA156-2 (7.0 g, 27.88 mmol) andethynyltrimethylsilane (3.2 g, 33.45 mmol, 1.2 eq) in toluene (70 mL)was added triethylamine (11.7 mL, 83.64 mmol, 3.0 eq). After purgingwith nitrogen for 10-15 min, Copper (I) iodide (0.530 g, 2.78 mmol, 0.1eq) and Bis (triphenylphosphine) palladium (II) dichloride (1.9 g, 2.78mmol, 0.1 eq) were added. After stirring at 120° C. for 16 h, thereaction mixture was diluted with water (350 mL) and extracted withethyl acetate (3×100 mL). The combined organic extracts were washed withbrine (270 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with 22% elution ethyl acetate in hexane to afford IntermediateAA156-3 (2.5 g, 33.42%) MS (ES): m/z=270.0 [M+H]⁺

Step-3 Synthesis of 5-bromo-6-ethynylpyridin-2-amine (IntermediateAA156-4)

To a solution of Intermediate AA156-3 (4.0 g, 14.81 mmol) in methanol (5mL) was added slowly aqueous 2N potassium hydroxide solution (40 mL).After stirring at RT for 3 h, the reaction mixture was diluted with icecold water (200 mL) and extracted with DCM (3×90 mL). The combinedorganic extracts were washed with brine, dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 17% elution ethyl acetate in hexaneto afford the title compound Intermediate AA156-4 (1.6 g, 54.65%) MS(ES): m/z=197.04 [M+H]⁺

Step-4 Synthesis of 5-bromo-6-(2-(dimethylamino)ethyl)pyridin-2-amine(Intermediate AA156-5)

To a solution of Intermediate AA156-4 (4.5 g, 22.84 mmol) anddimethylamine (9.0 g, 114.2 mmol, 5.0 eq) in ethanol (45 mL) was addedsodium cyanoborohydride (2.1 g, 34.26 mmol, 1.5 eq). After stirring at110° C. for 16 h, the reaction mixture was concentrated under reducedpressure to afford residue which was diluted with DCM and water. Theaqueous layer was basified with sodium hydroxide solution and extractedwith 20% methanol in DCM (3×80 mL). The combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure to afford Intermediate AA156-5 (4.0 g, 71.74%) MS (ES):m/z=245.04 [M+H]⁺

Step-5 Synthesis of6-(2-(dimethylamino)ethyl)-5-morpholinopyridin-2-amine (IntermediateAA156)

To a solution of Intermediate AA156-5 (2.0 g, 8.19 mmol) and morpholine(1.0 g, 12.29 mmol, 1.5 eq) in THF (20 mL) was added lithiumbis(trimethylsilyl)amide (4.7 mL, 24.57 mmol, 3.0 eq). After purgingwith nitrogen gas for 10 min. Pd₂(dba)₃ (0.150 g, 0.16 mmol, 0.02 eq)and Xantphos (0.378 g, 0.655 mmol, 0.08 eq) were added. After stirringat 70° C. for 16 h, the reaction mixture was filtered throughcelite-bed. The filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography eluting with 10% ethylacetate in hexane to afford the title compound Intermediate AA156 (0.9g, 43.88%) MS (ES): m/z=251.9 [M+H]⁺

Synthesis of tert-butyl((6-amino-3-(THF-3-yl)pyridin-2-yl)methyl)(methyl)carbamate(Intermediate-AA157)

Step-1 Synthesis ofN-(5-bromo-6-(hydroxymethyl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA157-1)

To a solution of the Intermediate AA149-1 (8 g, 26.7 mmol) in ethanol(60 mL) at 0° C. was added NaBH4 (3 g, 80.2 mmol, 3 eq) portion wise.After stirring at RT for 3 h, the reaction was quenched with water (100mL) and extracted into ethyl acetate (3×40 mL). The combined organiclayer was washed with brine, passed through a hydrophobic filter, andevaporated in vacuum to afford Intermediate AA157-1 (3.4 g,quantitative) which was used in the next step without purification. MS(ES): m/z 271.1[M+1]⁺

Step-2 Synthesis ofN-(5-bromo-6-((methylamino)methyl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA157-2)

To a solution of the Intermediate AA157-1 (3.4 g, 12.5 mmol) and N—Ndiisopropyl ethylamine (7.5 mL, 43.9 mmol, 3.5 eq) in acetonitrile (40mL) at 0° C. was added methane sulfonyl chloride (1.7 mL, 21.2 mmol, 1.7eq). After stirring for 20 min at 0° C. and then warming to RT for 40min, the reaction was quenched with water (100 mL) and extracted intoDCM (3×40 mL). The combined organic layer was washed with brine, passedthrough a hydrophobic filter, and concentrated under reduced pressure.The residue dissolved in acetonitrile (40 mL) was treated withmonomethyl amine hydrochloride (66 mL, 133 mmol, 10.0 eq) and potassiumcarbonate (18 g, 133 mmol, 10.0 eq). After stirring at 80° C. for 2 h,the reaction was quenched with water (100 mL) and extracted into DCM(3×40 mL). The combined organic layer was washed with brine, passedthrough a hydrophobic filter, and evaporated in vacuum. The residue waspurified by silica gel chromatography eluting with 30% ethylacetate/hexane to afford Intermediate AA157-2 (2.0 g, 56.12%). MS (ES):m/z 284.1[M+H]⁺

Step-3 Synthesis of tert-butyl((3-bromo-6-(cyclopropanecarboxamido)pyridin-2-yl)methyl)(methyl)carbamate(Intermediate AA157-3)

To a solution of Intermediate AA157-2 (1.6 g, 5.6 mmol) in DCM (40 mL)at 0° C. was treated with di-tert-butyl dicarbonate (1.4 gm, 6.7 mmol,1.2 eq) and DMAP (0.14 g, 1.1 mmol, 0.2 eq). After stirring at RT for 16h, the reaction mixture was diluted ethyl acetate (20 mL) and water (15mL). The organic layer was collected, and the aqueous phase wasextracted with ethyl acetate (2×30 mL). The combined organic extractswere washed with brine (10 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford Intermediate AA157-3 (2.2g, quantitative) which was used in the next step without purification.,MS (ES): m/z 384.2[M+H]⁺

Step-4 Synthesis of tert-butyl((6-(cyclopropanecarboxamido)-3-(furan-3-yl)pyridin-2-yl)methyl)(methyl)carbamate(Intermediate AA157-4)

To a solution of Intermediate AA157-3 (2.2 g, 5.7 mmol) in dioxane (20mL) and water (5 mL) were added furan-3-ylboronic acid (0.766 g, 6.8mmol, 1.2 eq) and potassium phosphate tribasic (3.6 g, 17.1 mmol, 3.0eq). After degassing with N2 for 15 min, X-Phos Pd G2 (0.45 g, 0.57mmol, 0.1 eq) was added. After stirring at 100° C. for 2 h, the reactionmixture was cooled at RT and diluted with ethyl acetate (20 mL) andwater (20 mL). The organic layer was collected, and the aqueous phasewas extracted with ethyl acetate (2×30 mL) The combined organic extractswere washed with brine (20 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 35% ethyl acetate gradient in hexane toafford Intermediate AA157-4 (2 g, 94%), MS (ES): m/z 371.4[M+H]⁺

Step-5 Synthesis of tert-butyl((6-(cyclopropanecarboxamido)-3-(THF-3-yl)pyridin-2-yl)methyl)(methyl)carbamate(Intermediate AA157-5)

To a solution of Intermediate AA157-4 (2 g, 5.31 mmol) in MeOH:THF(15:15 mL) at RT was added Pd(OH)₂(1.5 g), ammonium formate (1.4 g,21.5mmol,4.0 eq), and acetic acid (0.5 mL). After stirring at RT for 3 hwith H2 gas at atmospheric pressure, the reaction mixture was filtratethrough celite bed. The organic layer was evaporated in vacuum to affordIntermediate AA157-5 (3 g, quantitative) which was used in the next stepwithout purification. MS (ES): m/z 375.4[M+1]+

Step-6 Synthesis of tert-butyl((6-amino-3-(THF-3-yl)pyridin-2-yl)methyl)(methyl)carbamate(Intermediate AA157)

To a solution Intermediate AA157-5 (3 g, 8 mmol) in MeOH (15 mL) and H₂O(15 mL) was added NaOH (3.2 g, 8 mmol). After stirring at 70° C. for 2h, the reaction mixture was evaporated in vacuum, quenched with water(30 mL), and extracted by ethyl acetate (3×40 mL). The combined organiclayer was evaporated in vacuum to afford Intermediate AA157 (1.5 g,quantitative) which was used in the next step without purification. MS(ES): m/z 307.19[M+1]⁺

Synthesis of 1-(6-aminopyridin-2-yl)-4-(azetidin-1-yl)pyrrolidin-2-one(Intermediate AA158)

Step-1 Synthesis of 4-hydroxy-1-(6-nitropyridin-2-yl)pyrrolidin-2-one(Intermediate AA158-2)

To a solution of Intermediate AA158-1 (4 g, 39.5 mmol) andIntermediate-AA51-1 (6.3 g, 39.5 mmol) in 1, 4-dioxane (100 mL) wasadded Cs₂CO₃ (19.4 g, 59.3 mmol, 1.5 eq). After degassing under N2stream for 15 min, Pd₂(dba)₃ (1.8 g, 1.9 mmol, 0.05 eq) and Xantphos(2.3 g, 3.9 mmol, 0.1 eq) were added. After stirring at 100° C. and for4 h, the reaction mixture was cooled at RT and diluted with water (50mL) and 10% MeOH in DCM (100 mL). The organic layer was collected, andthe aqueous phase was extract with 10% MeOH in DCM (300 mL). Thecombined organic extracts were washed with brine (200 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography (70% ethyl acetate gradient inhexane). The residue obtained was then triturated with diethyl ether andthe resulting solid was collected by filtration to afford the titlecompound Intermediate AA158-2 (1 g, 11%). MS (ES): m/z=223.1 [M+2]+

Step-2 Synthesis of4-(azetidin-1-yl)-1-(6-nitropyridin-2-yl)pyrrolidin-2-one (IntermediateAA158-3)

To a solution of the Intermediate AA158-2 (1 g, 4.5 mmol) and N—Ndiisopropyl ethylamine (0.59 g, 5.8 mmol, 1.3 eq) in DCM (10 mL) at 0°C. was added methane sulfonyl chloride (0.67 g, 5.6 mmol, 1.3 eq). Afterstirring at RT stirred for 4 h, the reaction was quenched with water(100 mL) and extracted into DCM (3×40 mL). The combined organic layerwas washed with brine, passed through a hydrophobic filter, andconcentrated under reduced pressure. The residue was then dissolved inDMF (6 mL), and treated with azetidine (0.4 g, 6.9 mmol, 1.5 eq). Afterstirring at 130° C. for 4 h in microwave, the reaction was quenched withwater (100 mL) and extracted into ethyl acetate (3×40 mL). The combinedorganic layer was washed with brine, passed through a hydrophobicfilter, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography using 30% ethyl acetate gradientin hexane to afford Intermediate AA158-3 (0.180 g, 12%). MS (ES): m/z262 [M+H]⁺

Step-3 Synthesis of1-(6-aminopyridin-2-yl)-4-(azetidin-1-yl)pyrrolidin-2-one (IntermediateAA158)

To a solution of Intermediate AA158-3 (0.18 g) in THF (8 mL) was added10% Pd/c (0.05 g). After stirring at RT for 16 h with H2 gas atatmospheric pressure, the reaction mixture was filtered through celitebed. The organic layer was evaporated in vacuum to afford IntermediateAA158 (0.18 g, quantitative) which was used in the next step withoutpurification. MS (ES): m/z 232 [M+1]⁺

Synthesis of5-(2-(2-(cyclopropylamino)propan-2-yl)morpholino)pyridin-2-amine(Intermediate AA159)

Step-1 Synthesis of2-(4-(6-nitropyridin-3-yl)morpholin-2-yl)propan-2-amine (IntermediateAA159-1)

To a solution of Intermediate AA130-3 (2.5 g, 6.62 mmol) in DCM (20 mL)was added 4M HCL in dioxane (2 mL). After stirring at RT for 30 min, thereaction mixture was diluted with ice water (50 mL) and extracted withethyl acetate (3×30 mL). The combined organic layer was washed withbrine solution, dried over sodium sulfate, and concentrated underreduced pressure. The residue was purified by trituration using diethylether and pentane to afford Intermediate AA159-1 (1.5 g, 82%). MS (ES):m/z 267.1 [M+H]⁺

Step-2 Synthesis ofN-(2-(4-(6-nitropyridin-3-yl)morpholin-2-yl)propan-2-yl)cyclopropanamine(Intermediate AA159-2)

To a solution of Intermediate AA159-1 (1.4 g, 5.26 mmol) in methanol (20mL) with acetic acid (0.28 mL) and (1-ethoxycyclopropoxy)trimethylsilane(1.1 mL, 5.78 mmol, 1.1 eq). at 0° C. was added sodium cyanoborohydrideadded portion wise (1.65 g, 26.3 mmol, 5.0 eq). After stirring at 60° C.for 16 h, the reaction mixture was quenched with sodium bicarbonatesolution and extracted with DCM (3×50 mL). The combined organic layerwas washed with brine solution, dried over sodium sulfate, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 1.5% methanol in DCM to afford IntermediateAA159-2 (1.2 g, 74.51%). MS (ES): m/z 307.1 [M+H]⁺

Step-3. 5-(2-(2-(cyclopropylamino)propan-2-yl)morpholino)pyridin-2-amine(Intermediate AA159)

To a solution of Intermediate AA159-2 (1.4 g, 3.92 mmol) in methanol (20mL). was added 10% Pd/c (0.7 g) After stirring at RT for 1 h with H2 gasat atmospheric pressure, the reaction mixture was filtered throughcelite-bed and washed with 10% methanol DCM. The filtrate wasconcentrated under reduced pressure to afford Intermediate AA159 (1.0 g,92.37%). MS (ES): m/z 277.2 [M+H]⁺

Synthesis of6-(((2-methoxyethyl)(methyl)amino)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA160)

6-(((2-methoxyethyl)(methyl)amino)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA160) was prepared from tert-butyl(6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate (IntermediateAA145-6) and 2-methoxy-N-methylethan-1-amine in a similar fashion tothat procedure of step-6, step-7 and step-8 described in synthesis of5-cyclopentyl-6-((dimethylamino)methyl)pyridin-2-amine (IntermediateAA145) (0.550 g, quantitative %). m/z 266.1 [M+H]⁺

Synthesis of6-((isopropyl(methyl)amino)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA161)

6-((isopropyl(methyl)amino)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA161) was prepared from tert-butyl(6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate (IntermediateAA145-6) and N-methylpropan-2-amine in a similar fashion to thatprocedure of step-6, step-7 and step-8 described in synthesis of5-cyclopentyl-6-((dimethylamino)methyl)pyridin-2-amine (IntermediateAA145) (0.550 g, quantitative %). m/z 250.1 [M+H]⁺

Synthesis of2-(((6-amino-3-(THF-3-yl)pyridin-2-yl)methyl)(methyl)amino)ethan-1-ol(Intermediate-AA162)

2-(((6-amino-3-(THF-3-yl)pyridin-2-yl)methyl)(methyl)amino)ethan-1-ol(Intermediate-AA162) was prepared from tert-butyl(6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate (IntermediateAA145-6) and 2-(methylamino)ethan-1-ol in a similar fashion to thatprocedure of step-6, step-7 and step-8 described in synthesis of5-cyclopentyl-6-((dimethylamino)methyl)pyridin-2-amine (IntermediateAA145) (0.8 g, quantitative %). m/z 252.1 [M+H]⁺

Synthesis of6-(((S)-3-fluoropyrrolidin-1-yl)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA163)

6-(((S)-3-fluoropyrrolidin-1-yl)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA163) was prepared from tert-butyl(6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate (IntermediateAA145-6) and (S)-3-fluoropyrrolidine in a similar fashion to thatprocedure of step-6, step-7 and step-8 described in synthesis of5-cyclopentyl-6-((dimethylamino)methyl)pyridin-2-amine (IntermediateAA145) (0.8 g, quantitative %). m/z 265.3 [M+H]⁺

Synthesis of6-((cyclopropyl(methyl)amino)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA164)

6-((cyclopropyl(methyl)amino)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA164) was prepared from tert-butyl(6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate (IntermediateAA145-6) and N-methylcyclopropanamine in a similar fashion to thatprocedure of step-6, step-7 and step-8 described in synthesis of5-cyclopentyl-6-((dimethyl amino)methyl)pyridin-2-amine (IntermediateAA145) (0.75 g, 78.42%). m/z 248.1 [M+H]⁺

Synthesis of tert-butyl((6-amino-3-(THF-3-yl)pyridin-2-yl)methyl)(2,2-difluoroethyl)carbamate(Intermediate-AA165)

Step-1,2 Synthesis ofN-(6-(((2,2-difluoroethyl)amino)methyl)-5-(THF-3-yl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA165-1)

To a solution of the Intermediate AA149-4 (4 g, 15.2 mmol) and N—Ndiisopropyl ethylamine (7.8 mL, 45.78 mmol, 3.0 eq) in acetonitrile (40mL) at 0° C. was added methane sulfonyl chloride (1.7 mL, 22.89 mmol,1.5eq). After stirring for 20 min warming to RT and then stirring for 40min, the reaction was quenched with water (300 mL) and extracted withDCM (3×100 mL). The combined organic layer was washed with brine, passedthrough a hydrophobic filter, and concentrated under reduced pressure.To the residue dissolved in acetonitrile (40 mL) were added2,2-difluoroethan-1-amine (6.1 g, 76.3 mmol, 5.0 eq) and potassiumcarbonate (16.8 g, 122.08 mmol, 8.0 eq). After stirring at 80° C. for 16h, the reaction mixture was filtered through a celite bed, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography eluting with 15% ethyl acetate inhexane to afford Intermediate AA165-1 (2.2 g, 44.34%) as a yellow oil.MS (ES): m/z 326.2 [M+H]⁺

Step-3 Synthesis of tert-butyl((6-(cyclopropanecarboxamido)-3-(THF-3-yl)pyridin-2-yl)methyl)(2,2-difluoroethyl)carbamate(Intermediate AA165-2)

To a solution of Intermediate AA165-1 (2.4 g, 6.76 mmol) in DCM (25 mL)with triethylamine (2.8 g, 20.3 mmol, 3.0 eq) at 0° C. was addeddi-tert-butyl dicarbonate (4.4 g, 20.28 mmol, 3.0 eq). After stirring atRT for 5 h, the reaction mixture was diluted with ethyl acetate (100 mL)and water (50 mL). The organic layer was collected, and the aqueousphase was extracted with ethyl acetate (3×50 mL). The combined organicextracts were washed with brine (40 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 20% ethyl acetate in hexane to affordthe title compound Intermediate AA165-2 (1.5 g, 52.14%) as a brownsolid. MS (ES): m/z=426.2 [M+H]⁺

Step-4 Synthesis of tert-butyl((6-amino-3-(THF-3-yl)pyridin-2-yl)methyl)(2,2-difluoroethyl)carbamate(Intermediate AA165)

To a solution of Intermediate AA165-2 (1.5 g, 3.52 mmol) inmethanol:water (20 mL:5 mL) was added sodium hydroxide (1.6 g, 42.25mmol, 12 eq). After stirring at RT for 16 h, the reaction mixture wasconcentrated under reduced pressure. The residue was treated with water(30 mL), neutralized with 1N hydrochloric acid to pH-6-6.5 at 10° C. andextracted with DCM (3×30 mL). The combined organic layer was washed withbrine solution, dried over sodium sulfate, and concentrated underreduced pressure to afford Intermediate AA165 (1.2 g, quantitative). MS(ES): m/z 358.3 [M+H]⁺

Synthesis of6-(((R)-3-fluoropyrrolidin-1-yl)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA166)

6-(((R)-3-fluoropyrrolidin-1-yl)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA166) was prepared from tert-butyl(6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate (IntermediateAA145-6) and (R)-3-fluoropyrrolidine in a similar fashion to thatprocedure of step-6, step-7 and step-8 described in synthesis of5-cyclopentyl-6-((dimethylamino)methyl)pyridin-2-amine (IntermediateAA145) (0.75 g, quantitative %). m/z 266.1 [M+H]⁺

Synthesis of6-((methyl(oxetan-3-yl)amino)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA167)

6-((methyl(oxetan-3-yl)amino)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA167) was prepared from tert-butyl(6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate (IntermediateAA145-6) and N-methyloxetan-3-amine in a similar fashion to thatprocedure of step-6, step-7 and step-8 described in synthesis of5-cyclopentyl-6-((dimethylamino)methyl)pyridin-2-amine (IntermediateAA145) (0.650 g, quantitative %). m/z 264.1 [M+H]⁺

Synthesis of2-(1-(6-chloro-2-((dimethylamino)methyl)pyridin-3-yl)piperidin-3-yl)propan-2-ol(Intermediate AA168)

Step-1 Synthesis of tert-butyl3-(2-hydroxypropan-2-yl)piperidine-1-carboxylate (Intermediate AA168-2)

To a solution of Intermediate AA168-1 (5.0 g, 20.57 mmol) in THF (50 mL)at 0° C. was added methyl magnesium bromide 3M solution in diethyl ether(50 mL). After stirring at 0° C. for 15-20 min, the reaction mixture wasquenched slowly in water (200 mL) and extracted with ethyl acetate (3×70mL). The combined organic layer was washed with brine solution, driedover sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by column chromatography eluting with 30% ethylacetate in hexane to afford Intermediate AA168-2 (5.0 g, 99.98%). MS(ES): m/z 244.1 [M+H]⁺

Step-2 Synthesis of 2-(piperidin-3-yl)propan-2-ol (Intermediate AA168-3)

To a solution of Intermediate AA168-2 (5.0 g, 20.57 mmol) in DCM (50 mL)was added trifluoroacetic acid (5 mL). After stirring at RT for 1 h, thereaction mixture was concentrated under reduced pressure, diluted withsodium bicarbonate solution, and extracted with ethyl acetate (3×40 mL).The combined organic layer was washed with brine solution, dried oversodium sulfate, and concentrated under reduced pressure to affordIntermediate AA168-3 (5.0 g, quantitative %). MS (ES): m/z 144.1 [M+H]⁺

Step-3 Synthesis of5-chloro-2-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)benzaldehyde(Intermediate AA168-4)

To a solution of 6-chloro-3-fluoropicolinaldehyde (1.0 g, 6.28 mmol) andIntermediate AA168-3 (2.6 g, 18.84 mmol, 3.0 eq) and in DMF (10 mL) wasadded potassium carbonate (4.3 g, 31.4 mmol, 5.0 eq). After stirring at100° C. for 1 h, the reaction mixture was cooled to RT, diluted with icecold water (80 mL) and extracted with ethyl acetate (3×40 mL). Thecombined organic layer was washed with brine solution, dried over sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by column chromatography eluting with 20% ethyl acetate inhexane to afford Intermediate AA168-4 (1.5 g, 84.63%). MS (ES): m/z282.1 [M+H]⁺

Step-4 Synthesis of2-(1-(6-chloro-2-((dimethylamino)methyl)pyridin-3-yl)piperidin-3-yl)propan-2-ol(Intermediate AA168)

To a solution of Intermediate AA168-4 (1.5 g, 5.33 mmol) in 1,2-dichloroethane (20 mL) was added acetic acid (2 mL) at 0° C.Dimethylamine gas was purged in reaction mixture for 1 h. Then Sodiumtriacetoxyborohydride (10.0 g) was added portion wise into the reactionmixture. After stirring at RT for 16 h, the reaction mixture was dilutedwith water (100 mL) and extracted with DCM (3×50 mL). The combinedorganic layer was washed with brine solution, dried over sodium sulfate,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 6% ethyl acetate in hexane to affordIntermediate AA168 (0.9 g, 54.40%). MS (ES): m/z 312.2 [M+H]⁺

Synthesis of 4-(2-(6-chloropyridin-3-yl)propan-2-yl)morpholine(Intermediate AA169)

Step-1 Synthesis of 2-(6-chloropyridin-3-yl)propan-2-amine (IntermediateAA169-2)

To freshly dried cerium (III) chloride (35.6 g) (dried at 140° C. for 4h under vacuum) was added at RT dry THF (450 mL) under argon. Afterstirring at RT for 16 h, the reaction mixture was cool at −78° C. andMeLi (120 mL) was added dropwise. After stirring at −78° C. for 2 h,6-chloronicotinonitrile (2 g) in THF was added at −78° C. After stirringat −78° C. for 2 h, the reaction mixture was diluted with water (50 mL)and 10% MeOH in DCM (100 mL). The organic layer was collected, and theaqueous phase was extract with 10% MeOH in DCM (300 mL). The combinedorganic extracts were washed with brine (200 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography (2% MeOH gradient in DCM) to affordIntermediate AA169-2 (1.5 g, 61%). MS (ES): m/z=170.6 [M+2]⁺

Step-2 Synthesis of 4-(2-(6-chloropyridin-3-yl)propan-2-yl)morpholine(Intermediate AA169)

To a solution of Intermediate AA169-2 (1.5 g, 8.7 mmol)) in DMF (10 mL)were added 1-bromo-2-(2-bromoethoxy)ethane (3.5 g, 14.9 mmol, 1.7 eq)and N—N diisopropyl ethylamine (3.4 g, 26.3 mmol, 3 eq). After stirringat 120° C. for 16 h, the reaction was quenched with water (100 mL) andextracted into ethyl acetate (3×40 mL). The combined organic layer waswashed with brine, passed through a hydrophobic filter, and concentratedunder reduced pressure. The residue was purified by silica gelchromatography using 100% DCM to afford Intermediate AA169 (1.2 g,56%).MS (ES): m/z 240.7 [M+H]⁺

Synthesis of tert-butyl((6-amino-3-(THF-3-yl)pyridin-2-yl)methyl)(2,2,2-trifluoroethyl)carbamate(Intermediate-AA171)

Step-1, 2 Synthesis ofN-(5-(THF-3-yl)-6-4(2,2,2-trifluoroethyl)amino)methyl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA171-1)

To a solution of Intermediate AA145-6 (4 g, 15.2 mmol) and N—Ndiisopropyl ethylamine (7.8 mL, 45.78 mmol, 3.0 eq) in acetonitrile (40mL) at 0° C. was added methane sulfonyl chloride (1.7 mL, 22.89 mmol,1.5eq). After stirring for 20 min warming to RT and stirring for 40 min atRT, the reaction was quenched with water (300 mL) and extracted into DCM(3×100 mL). The combined organic layer was washed with brine, passedthrough a hydrophobic filter, and concentrated under reduced pressure.The residue was then dissolved in acetonitrile (40 mL), and treated with2,2,2-trifluoroethan-1-amine (7.5 g, 76.3 mmol, 5.0 eq) and potassiumcarbonate (16.8 g, 122.08 mmol, 8.0 eq). After stirring at 80° C. for 16h, the reaction mixture was filtered through a celite bed, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography using 15% ethyl acetate in hexaneto afford Intermediate AA171-1 (2.4 g, 45.84%) as a yellow oil. MS (ES):m/z 344.2 [M+H]⁺

Step-3 synthesis of tert-butyl((6-(cyclopropanecarboxamido)-3-(THF-3-yl)pyridin-2-yl)methyl)(2,2,2-trifluoroethyl)carbamate(Intermediate AA171-2)

To a solution of Intermediate AA171-1 (2.4 g, 6.97 mmol) in DCM (25 mL)with triethylamine (2.9 g, 20.91 mmol, 3.0 eq) at 0° C. was addeddi-tert-butyl dicarbonate (4.5 g, 20.9 mmol, 3.0 eq). After stirring atRT for 5 h, the reaction mixture was diluted with ethyl acetate (100 mL)and water (50 mL). The organic layer was collected, and the aqueousphase was extracted with ethyl acetate (3×50 mL). The combined organicextracts were washed with brine (40 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 25% ethyl acetate in hexane to affordthe title compound Intermediate AA171-2 (1.5 g, 48.39%) as a brownsolid. MS (ES): m/z=444.3 [M+H]⁺

Step-4 synthesis of tert-butyl((6-amino-3-(THF-3-yl)pyridin-2-yl)methyl)(2,2,2-trifluoroethyl)carbamate(Intermediate AA171)

To a solution of Intermediate AA171-2 (1.2 g, 2.70 mmol) inmethanol:water (20 mL:5 mL) was added sodium hydroxide (1.3 g, 32.50mmol, 12 eq). After stirring at RT for 16 h, the reaction mixture wasconcentrated under reduced pressure. The residue was dissolved in water(30 mL), neutralized with 1N hydrochloric acid to pH-6.5 and extractedwith DCM (3×30 mL). The combined organic layer was washed with brinesolution, dried over sodium sulfate, and concentrated under reducedpressure to afford Intermediate AA171 (1.3 g, quantitative %). MS (ES):m/z 376.4 [M+H]⁺

Synthesis of 6-(azetidin-1-ylmethyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA173)

Step-1 synthesis of tert-butyl(5-bromo-6-(bromomethyl)pyridin-2-yl)carbamate (Intermediate AA173-2)

To a solution of the Intermediate-AA173-1 (12 g, 31.08 mmol) in carbontetrachloride (20 mL) were added N-bromosuccinimide (6.6 g, 37.29 mmol,1.2 eq) and benzoyl peroxide (0.752 g, 3.10 mmol, 0.1 eq). Afterstirring at 100° C. for 3 h, the reaction mixture was cooled to RT,diluted with water (500 mL), and extracted into DCM (4×100 mL). Thecombined organic extracts were washed with brine (200 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure to affordIntermediate AA173-2 (5 g, quantitative %) which was used in the nextstep without further purification as a yellow oil. MS (ES): m/z 367.94[M+H]⁺

Step-2 synthesis of tert-butyl(6-(azetidin-1-ylmethyl)-5-bromopyridin-2-yl) carbamate (IntermediateAA173-3)

To a solution of Intermediate AA173-2 (5.0 g, 8.19 mmol) in DMF (30 mL)were added azetidine (1.1 g, 20.47 mmol, 2.5 eq) and potassium carbonate(3.3 g, 24.57 mmol, 3.0 eq). After stirring at 100° C. for 2 h, reactionmixture was cooled to RT, diluted with ice cold water (250 mL) andextracted into DCM (3×100 mL). The combined organic extracts were washedwith brine (100 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with 3% elution methanol in DCM to afford Intermediate AA173-3(3.5 g, 73.77%) MS (ES): m/z 341.07 [M+H]⁺

Step-3 synthesis of tert-butyl(6-(azetidin-1-ylmethyl)-5-(furan-3-yl)pyridin-2-yl)carbamate(Intermediate AA173-4)

To a solution of Intermediate AA173-3 (3.5 g, 7.91 mmol) in 1,4-dioxane: water (35 mL: 7 mL) was added furan-3-ylboronic acid (1.3 g,11.86 mmol, 1.5 eq), Cs₂CO₃ (1.5 g, 4.74 mmol, 3.0 eq) and potassiumphosphate tribasic (5.0 g, 23.73 mmol, 3.0 eq). After degassing under N2stream for 15 min, Xphose PdG2, (0.621 g, 0.791 mmol, 0.1 eq) was added.After stirring at 100° C. for 30 min microwave, the reaction mixture wascooled to RT, diluted water (100 mL) and extracted with ethyl acetate(40 mL). The organic layer was collected, and the aqueous phase wasextracted with ethyl acetate (2×40 mL). The combined organic extractswere washed with brine (50 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 7% methanol in DCM to afford the titlecompound Intermediate AA173-4 (2.2 g, 64.74%) as a brown solid. MS (ES):m/z=430.23 [M+2]⁺

Step-4, 5 synthesis of6-(azetidin-1-ylmethyl)-5-(THF-3-yl)pyridin-2-amine (Intermediate AA173)

To a solution of Intermediate AA173-4 (2.2 g, 5.12 mmol) in methanol (15mL) and THF (7 mL) were added ammonium formate (1.2 g, 20.48 mmol, 4.0eq), acetic acid (1.1 mL, 0.5v) and 10% palladium hydroxide on carbon(2.2 g). After stirring at 60° C. for 16 h with 20 psi pressure inhydrogenator, the reaction mixture was filtered through Celite bed, andthe filtrate was concentrated under reduced pressure. The residue waspurified by combi-flash Colum chromatography eluting with 7%methanol/DCM to afford intermediate.

To this intermediate dissolved in DCM (20 mL) was added trifluoroaceticacid (10 mL). After stirring at RT at 30 min, the reaction mixture wasdiluted with sat. NaHCO₃(15 mL) and the aqueous phase was extracted with10% methanol/DCM with ammonia (3×50 mL). The combined organic extractswere washed with brine (50 mL), dried over Na₂SO₄ and concentrated underreduced to afford Intermediate AA173 (0.8 g, 66.99%) which was used inthe next step without further purification. MS (ES): m/z 234.1 [M+1]⁺

Synthesis of 6-((ethyl(methyl)amino)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA174)

Step-1 & Step-2 synthesis ofN-(6-((ethyl(methyl)amino)methyl)-5-(THF-3-yl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA174-1)

To a solution of Intermediate AA149-4 (1.8 g, 6.87 mmol) in DCM (20 mL)at 0° C. with triethylamine (2.3 mL, 16.48 mmol, 2.4 eq) was addedmethane sulfonyl chloride (1.0 mL, 13.74 mmol, 2.0 eq) dropwise. Afterstirring at RT for 3 h, the reaction mixture was diluted with water (50mL), washed with sodium bicarbonate solution, and extracted with DCM(3×20 mL). The combined organic extracts were washed with brine (50 mL),dried over Na₂SO₄, filtered, and concentrated under reduced pressure(2.3 g). To the mesylate intermediate (2.3 g, 6.76 mmol) in acetonitrile(20 mL) was added potassium carbonate (9.3 g, 67.6 mmol, 10.0 eq) andN-methylethanamine (2.0 g, 33.8 mmol, 5.0 eq). After stirring at RT for10 h at 70° C., the reaction mixture was diluted with water (80 mL) andextracted with DCM (3×30 mL). The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure to afford Intermediate AA174-1 which was used in next stepwithout purification. (1.5 g, 93.49%), MS (ES): m/z 304.2 [M+H]⁺

Step-3 synthesis of6-((ethyl(methyl)amino)methyl)-5-(THF-3-yl)pyridin-2-amine (IntermediateAA174)

To a solution of Intermediate AA174 (1.5 g, 4.95 mmol) in methanol (20mL) and water (5 mL) was added sodium hydroxide (2.0 g, 49.5 mmol, 10.0eq). After stirring at 50° C. for 12 h, the reaction mixture was cooledto RT, concentrated under reduced pressure to remove methanol, dilutedin water (50 mL), and extracted with 5% methanol in DCM (3×20 mL). Thecombined organic extracts were washed with brine (60 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure to affordIntermediate AA174 (1.2 g, quantitative %), MS (ES): m/z 236.1 [M+H]⁺

Synthesis of 6-(2-(dimethylamino)ethyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA175)

Step-1 Synthesis of6-(2-(dimethylamino)ethyl)-5-(furan-3-yl)pyridin-2-amine (IntermediateAA175-1)

To a solution of Intermediate AA156-5 (2.0 g, 8.1 mmol)) in dioxane (30mL) and water (10 mL) were added furan-3-ylboronic acid (0.766 g, 9.8mmol, 1.2 eq) and potassium phosphate tribasic (5.5 g, 26 mmol, 3.2 eq.After degassing with N2 for 15 min, PdCl₂(dppf)DCM (0.66 g, 0.81 mmol,0.1 eq) was added. After stirring at 120° C. for 1 h, the reactionmixture was cooled at RT and diluted with ethyl acetate (20 mL) andwater (20 mL). The organic layer was collected, and the aqueous phasewas extracted with ethyl acetate (2×30 mL). The combined organicextracts were washed with brine (20 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography to afford Intermediate AA175-1 (1 g, 52.7%), MS(ES): m/z 231.3 [M+H]+

Step-2 Synthesis of6-(2-(dimethylamino)ethyl)-5-(THF-3-yl)pyridin-2-amine (IntermediateAA175)

To a solution of Intermediate AA175-1 (2 g, 43 mmol) in methanol:THF (30mL: 10 mL) was added Pd(OH)₂ (1.0 g), ammonium format (1.1 g), andacetic acid (1 mL). After stirring at RT for 12 h with H2 gas atatmospheric pressure, the reaction mixture was filtrate through celitebed, and the filtrate was evaporating in vacuum. The residue waspurified by silica gel chromatography eluting with 10% Et₃N/ethylacetate to afford Intermediate AA175 (0.8 g, 78%) MS (ES): m/z 235.3[M+H]⁺

Synthesis of6-((3-fluoroazetidin-1-yl)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA176)

6-((3-fluoroazetidin-1-yl)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA176) was prepared from tert-butyl(6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate (IntermediateAA145-6) and 3-fluoroazetidine in a similar fashion to that procedure ofstep-6, step-7 and step-8 described in synthesis of5-cyclopentyl-6-((dimethylamino)methyl)pyridin-2-amine (IntermediateAA145) (0.750 g, quantitative %). m/z 251.2 [M+H]⁺

Synthesis of 1-((6-amino-3-(THF-3-yl)pyridin-2-yl)methyl)azetidin-3-ol(Intermediate-AA177)

1-((6-amino-3-(THF-3-yl)pyridin-2-yl)methyl)azetidin-3-ol(Intermediate-AA176) was prepared from tert-butyl(6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate (IntermediateAA145-6) and azetidin-3-ol in a similar fashion to that procedure ofstep-6, step-7 and step-8 described in synthesis of5-cyclopentyl-6-((dimethylamino)methyl)pyridin-2-amine (IntermediateAA145) (0.750 g, quantitative %). m/z 249.2 [M+H]⁺

Synthesis of2-(4-(6-amino-2-((dimethylamino)methyl)pyridin-3-yl)morpholin-2-yl)propan-2-ol(Intermediate-AA178)

Step-1 synthesis of tert-butyl2-(2-hydroxypropan-2-yl)morpholine-4-carboxylate (Intermediate AA178-2)

A solution of Intermediate AA125-1 (10 g, 38.61 mmol) in THF (100 mL) at0° C. was added dropwise methyl magnesium bromide solution (3.0M indiethyl ether) (100 mL) in to the reaction mixture at 0° C. and stirredfor 15 min at RT. The reaction mixture was quenched in water (500 mL)and extracted with ethyl acetate (3×100 mL). The combined organicextracts were washed with brine (200 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure to afford Intermediate AA178-2(12.0 g, quantitative %) which was used in the next step without furtherpurification. MS (ES): m/z 245.3 [M+H]⁺

Step-2 synthesis of 2-(morpholin-2-yl)propan-2-ol (Intermediate AA178-3)

To a solution of Intermediate AA178-2 (10.0 g, 40.81 mmol) in DCM (100mL) at 0° C. was added dropwise TFA (35 mL). After stirring at RT for 30min, the reaction mixture was concentrated under reduced pressure andthen extracted with DCM (250 mL). The organic layer was concentratedunder reduced pressure to afford Intermediate AA178-3 (13 g,quantitative %) which was used in the next step without furtherpurification. MS (ES): m/z 146.1 [M+H]⁺

Step-3 synthesis of6-chloro-3-(2-(2-hydroxypropan-2-yl)morpholino)picolinaldehyde(Intermediate AA178-4)

To a solution of the Intermediate AA178-3 (9.0 g, 61.64 mmol) and6-chloro-3-fluoropicolinaldehyde (10.78 g, 67.80 mmol, 1.3 eq) in DMF(90 mL) was added potassium carbonate (25.51 g, 184.92 mmol, 3.0 eq).After stirring for 4 h at 100° C., the reaction mixture was quenchedwith water (500 mL) and extracted with ethyl acetate (3×150 mL). Thecombined organic extracts were washed with brine (250 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography eluting with 1.2% elution methanolin DCM to afford Intermediate AA178-4 (8.0 g, 45.33%) MS (ES): m/z 285.1[M+H]⁺

Step-4 synthesis of2-(4-(6-chloro-2-((dimethylamino)methyl)pyridin-3-yl)morpholin-2-yl)propan-2-ol(Intermediate AA178-5)

To a solution of Intermediate AA178-4 (3.1 g, 10.95 mmol) in1,2-dichloroethane (35 mL) was added acetic acid (2 mL) at RT. Afterbubbling dimethylamine gas in the reaction mixture for 45 min, sodiumtriacetoxyborohydride (16.1 g, 76.65 mmol, 7.0 eq) was added portionwise. After stirring at RT for 16 h, the reaction mixture was quenchedin water (100 mL) and extracted with DCM (3×40 mL). The combined organicextracts were washed with brine (100 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 50% ethyl acetate in hexane to affordIntermediate AA178-5 (2.5 g, 73.17%) MS (ES): m/z 314.1 [M+H]⁺

Step-5 synthesis ofN-(6-((dimethylamino)methyl)-5-(2-(2-hydroxypropan-2-yl)morpholino)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA178-6)

To a solution of Intermediate AA178-5 (2.5 g, 7.98 mmol) in 1,4-dioxane(20 mL) were added 1-cyclopropanecarboxamide (1.2 g, 14.37 mmol, 1.8 eq)and potassium carbonate (3.3 g, 23.94 mmol, 3.0 eq). After degassingunder N2 stream for 15 min, Xantphos (0.922 g, 1.59 mmol, 0.2 eq) andPd₂(dba)₃ (0.730 g, 0.79 mmol, 0.1 eq) were added. After stirring at110° C. for 1 h, the reaction mixture was cooled to RT, diluted water(70 mL) and extracted with ethyl acetate (2×40 mL). The combined organicextracts were washed with brine (80 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 2% methanol gradient in DCM to affordIntermediate AA178-6 (2.0 g, 69.26%) MS (ES): m/z=363.2 [M+H]⁺

Step-6 synthesis of 2-(4-(6-amino-2-((dimethylamino)methyl)pyridin-3-yl)morpholin-2-yl)propan-2-ol (Intermediate AA178)

To a solution of Intermediate AA178-6 (1.9 g, 5.24 mmol) inmethanol:water (20 mL:5 mL) was added sodium hydroxide (2.0 g, 52.4mmol, 10 eq). After stirring at RT for 16 h, the reaction mixture wasconcentrated under reduced pressure. The residue was diluted with water(30 mL), neutralized with 1N hydrochloric acid to pH-6.5 and extractedwith DCM (3×30 mL). The combined organic layer was washed with brinesolution, dried over sodium sulfate, and concentrated under reducedpressure to afford Intermediate AA178 (1.2 g, quantitative %). MS (ES):m/z 295.2 [M+H]⁺

Synthesis of 2-chloro-N,N-dimethyl-5,6,7,8-tetrahydroquinolin-8-amine(Intermediate-AA179)

Step-1 synthesis of 2-chloro-5,6,7,8-tetrahydroquinolin-8-ol(Intermediate AA179-2)

To a solution of Intermediate AA179-1 (1.0 g, 5.52 mmol) in ethanol (10mL) was added portion wise sodium borohydride (0.626 g, 16.56 mmol, 3.0eq). After stirring at 60° C. for 30 min, the reaction was diluted withice cold water (80 mL) and extracted into ethyl acetate (3×35 mL). Thecombined organic layer was washed with brine, filtered, and concentratedunder reduced pressure. The residue was purified by silica gelchromatography eluting with 30% ethyl acetate in hexane to affordIntermediate AA179-2 (0.8 g, 79.12%). MS (ES): m/z 184.05 [M+H]⁺

Step-2 synthesis of2-chloro-N,N-dimethyl-5,6,7,8-tetrahydroquinolin-8-amine (IntermediateAA179)

To a solution of Intermediate AA179 (0.8 g, 4.37 mmol) in DCM (8 mL) at0° C. with N, N-Diisopropylethylamine (2.6 mL, 15.29 mmol, 3.5 eq) wasadded methane sulfonyl chloride (0.5 mL, 6.55 mmol, 1.5 eq) dropwise.After stirring at RT for 30 min, the reaction mixture was diluted withwater (40 mL), washed with sodium bicarbonate solution, and extractedwith DCM (3×20 mL). The combined organic extracts were washed withbrine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure (0.65 g). To the mesylate intermediate (0.65 g, 2.49 mmol)dissolved in acetonitrile (7 mL) was added N,N-diisopropylethylamine(1.3 mL, 7.47 mmol, 3.0 eq) and N-methylethanamine (1.0 g, 12.45 mmol,5.0 eq). After stirring at RT for 6 h at 90° C., the reaction mixturewas diluted with ice cold water (10 mL) and extracted with DCM (3×25mL). The combined organic extracts were washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography eluting with 4% methanol inDCM to afford Intermediate AA179 (1.0 gg, 92.05%) as a yellow oil. MS(ES): m/z 211.1 [M+H]⁺

Synthesis of 6-amino-3-(THF-3-yl)pyridin-2-yl)methanol(Intermediate-AA180)

Step-1 synthesis of 6-amino-3-(THF-3-yl)pyridin-2-yl)methanol(Intermediate AA180)

To a solution of Intermediate AA145-6 (1.0 g, 5.15 mmol) in DCM (15 mL)at 0° C. was added TFA (8 mL). After stirring at RT for 1 h, thereaction mixture was evaporated in vacuum to afford Intermediate AA180(0.750 g, quantitative) which was used in the next step without furtherpurification. MS (ES): m/z 194 [M+1]⁺

Synthesis of tert-butyl4-(6-amino-3-(THF-3-yl)pyridin-2-yl)piperazine-1-carboxylate(Intermediate-AA181)

Step-1 synthesis of N-benzyl-5-bromo-6-chloropyridin-2-amine(Intermediate AA181-2)

To a solution of Intermediate AA181-1 (15 g, 72.3 mmol) was addedbenzaldehyde (11.5 g,10.84 mmol,1.5 eq) in acetic acid (15 mL) and DCE(300 mL). After stirring at RT for 2 h, sodium triacetoxyborohydride(61.3 g, 139.5 mmol, 6.0 eq) was added portion wise. After stirringovernight, the reaction mixture was quenched with water (300 mL) andextracted by EtOAc (2×100 mL). The combined organic layer was washedwith brine (100 mL), dried with Na₂SO₄, and concentrated under reducedpressure. The residue was purified by column chromatography (5-10%gradient elution with ethyl acetate in Hexane) to affordIntermediate-AA181-2. (15 g, 98%), MS (ES): m/z 297[M+1]⁺

Step-2 synthesis of N-benzyl-6-chloro-5-(furan-3-yl)pyridin-2-amine(Intermediate AA181-3)

To a solution of Intermediate AA181-2 (5 g, 16.80 mmol) andfuran-3-ylboronic acid (11.5 g,10.84 mmol,1.5 eq) in dioxane (80 mL) andwater (20 mL) was added K₃PO₄ (8.9 g, 43.0 mmol, 2.5 eq). Afterdegassing under argon gas atmosphere for 10 min, Pd(dppf)Cl₂ (1.37 g,16.82 mmol, 0.1 eq) was added. After stirring at 100° C. for 2 h, thereaction mixture was quenched with water (300 mL) and extracted by EtOAc(2×100 mL). The combined organic layer was washed with brine (100 mL),dried with Na₂SO₄, filtered, and concentrated under reduced pressure toafford Intermediate AA181-3 (2.1 g, 90%), MS (ES): m/z 284 [M+1]⁺

Step-3 synthesis of tert-butyl4-(6-(benzylamino)-3-(furan-3-yl)pyridin-2-yl)-3-oxopiperazine-1-carboxylate(Intermediate AA181-4)

To a solution of Intermediate AA181-3 (0.520 g, 18.30 mmol) andtert-butyl 3-oxopiperazine-1-carboxylate (0.733 g,36.55 mmol,2 eq) indioxane (10 mL) was added K₂CO₃ (0.758 g, 35.44 mmol, 3 eq). Afterstirring under argon gas atmosphere for 10 min, CuI (0.697 g, 36.55mmol, 0.1 eq) and DMEDA (0.4 mL) were added. After stirring at 120° C.for 48 h, the reaction mixture was quenched with water (300 mL) andextracted by EtOAc (2×100 mL). The combined organic layer was washedwith brine (100 mL), dried with Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatography (23%gradient elution Ethyl acetate in Hexane) to afford Intermediate-AA181-4(0.140 g crude, 95%), MS (ES): m/z 448[M+1]⁺

Step-4 synthesis of tert-butyl4-(6-(benzylamino)-3-(furan-3-yl)pyridin-2-yl)piperazine-1-carboxylate(Intermediate AA181-5)

To a solution of Intermediate AA181-4 (0.578 g, 12.70 mmol,1.0 eq) inTHF (20 mL) was added DMS-Borane complex (0.965 g, 12.70 mmol, 10.0 eq).The reaction mixture was stirred at 20-25° C. for 3 h. After completionof reaction, diluted with sodium bicarbonate solution added slowlyexothermicity compound and extracted into ethyl acetate and the combinedorganic extracts were washed with brine, dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography (20% ethyl acetate gradient in hexane) to affordIntermediate AA181-5 (0.580 g, 98%), MS (ES): m/z 434 [M+1]⁺

Step-5 synthesis oftert-butyl4-(6-amino-3-(THF-3-yl)pyridin-2-yl)piperazine-1-carboxylate(Intermediate AA181)

To a solution of Intermediate AA181-5 (0.580 g, 13.30 mmol) in THF (5.8mL) with acetic acid (0.4 mL) and ammonium formate (0.169 g, 26.7 mmol,2.0 eq) was added palladium hydroxide (1.0 g) in autoclave reaction at20 psi. After stirring overnight at RT for, the reaction mixturefiltered through celite bed. The filtrate was concentrated and purifiedby column chromatography (2% methanol gradient in DCM) to affordIntermediate AA181 (0.120 g, 94%). MS (ES): m/z=348 [M+H]⁺

Synthesis of1-(6-chloro-2-((dimethylamino)methyl)pyridin-3-yl)piperidin-4-ol(Intermediate-AA182)

Step-1 synthesis of 6-chloro-3-(4-hydroxypiperidin-1-yl)picolinaldehyde(Intermediate AA182-1)

To a solution of Intermediate AA135-1 (1.0 g, 6.28 mmol) andpiperidin-4-ol (1.0 g, 10.04 mmol, 1.6 eq) in DMF (10 mL) was addedpotassium carbonate (2.6 g, 18.84 mmol, 3.0 eq). After stirring at 100°C. for 1 h, the reaction mixture was cooled to RT, diluted with ice coldwater (100 mL) and extracted with ethyl acetate (3×40 mL). The combinedorganic extracts were washed with brine (80 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography 30% ethyl acetate gradient in hexaneto afford Intermediate AA182-1 (1.2 g, 79.54%), MS (ES): m/z 241.07[M+H]⁺

Step-2 synthesis of1-(6-chloro-2-((dimethylamino)methyl)pyridin-3-yl)piperidin-4-ol(Intermediate AA182)

To a cooled solution of Intermediate AA182-1 (1.2 g, 5.00 mmol) in1,2-dichloroethane (20 mL) was added acetic acid (2.4 mL) at 0° C. Afterbubbling dimethylamine gas for 30 min, sodium triacetoxyborohydride (7.4g, 35 mmol, 7.0 eq) was added portion wise. After stirring at RT for 16h, the reaction mixture was diluted with ice cold water (100 mL) andextracted with DCM (4×40 mL). The combined organic extracts were washedwith brine (90 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatography 3%methanol gradient in DCM to afford Intermediate AA182 (0.450 g, 33.46%),MS (ES): m/z 270.2 [M+H]⁺

Synthesis ofS)-1-((6-amino-34(R)-THF-3-yl)pyridin-2-yl)methyl)pyrrolidin-3-ol(Intermediate-AA183)

(S)-1-((6-amino-3-((R)-THF-3-yl)pyridin-2-yl)methyl)pyrrolidin-3-ol(Intermediate-AA183) was prepared from tert-butyl(6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate (IntermediateAA145-6) and (S)-pyrrolidin-3-ol in a similar fashion to that procedureof step-6, step-7 and step-8 described in synthesis of5-cyclopentyl-6-((dimethyl amino)methyl)pyridin-2-amine (IntermediateAA145) (0.5 g). m/z 278.1 [M+H]⁺

Synthesis of6-4(R)-3-methoxypyrrolidin-1-yl)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA184)

6-(((R)-3-methoxypyrrolidin-1-yl)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA184) was prepared from tert-butyl(6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate (IntermediateAA145-6) and (R)-3-methoxypyrrolidine in a similar fashion to thatprocedure of step-6, step-7 and step-8 described in synthesis of5-cyclopentyl-6-((dimethylamino)methyl)pyridin-2-amine (IntermediateAA145) (0.6 g, quantitative %). m/z 278.1 [M+H]⁺

Synthesis of1-(6-chloro-2-((dimethylamino)methyl)pyridin-3-yl)-4-(methoxymethyl)piperidin-4-ol(Intermediate-AA185)

Step-1 synthesis of6-chloro-3-(4-hydroxy-4-(methoxymethyl)piperidin-1-yl)picolinaldehyde(Intermediate AA185-1)

To a solution of Intermediate AA135-1 (2.5 g, 15.72 mmol) and4-(methoxymethyl)piperidin-4-ol (3.2 g, 22.01 mmol, 1.4 eq)) in DMF (25mL) was added potassium carbonate (4.3 g, 31.44 mmol, 2.0 eq). Afterstirring at 80° C. for 1 h, the reaction mixture was cooled to RT,diluted water (150 mL) and extracted with ethyl acetate (3×60 mL). Thecombined organic extracts were washed with brine (180 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography eluting with 35% ethyl acetategradient in hexane to afford Intermediate AA185-1) (3.0 g, 67.24%), MS(ES): m/z 285.1 [M+H]⁺

Step-2 synthesis of1-(6-chloro-2-((dimethylamino)methyl)pyridin-3-yl)-4-(methoxymethyl)piperidin-4-ol(Intermediate AA185)

To a solution of Intermediate AA185-1 (3.0 g, 10.56 mmol) in1,2-dichloroethane (30 mL) at 0° C. was added acetic acid (6 mL). Afterbubbling dimethylamine gas for 30 min, sodium triacetoxyborohydride(15.6 g, 73.92 mmol, 7.0 eq) was added portion wise. After stirring atRT for 16 h, the reaction mixture was diluted with ice cold water (250mL) and extracted with DCM (4×40 mL). The combined organic extracts werewashed with brine (90 mL), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by columnchromatography 27% ethyl acetate gradient in hexane to affordIntermediate AA185 (2.4 g, 72.59%), MS (ES): m/z 314.1 [M+H]⁺

Synthesis ofN-((6-chloro-3-morpholinopyridin-2-yl)methyl)-N-ethylethanamine(Intermediate-AA186)

Step-1 synthesis of 6-chloro-3-morpholinopicolinaldehyde (IntermediateAA186-1)

To a solution of Intermediate AA135-1 (1.0 g, 6.28 mmol) and morpholine(1.0 g, 12.56 mmol, 2.0 eq) in DMF (10 mL) was added potassium carbonate(2.6 g, 18.84 mmol, 3.0 eq). After stirring at 100° C. for 1 h, thereaction mixture was cooled to RT, diluted with ice cold water (100 mL)and extracted with ethyl acetate (3×40 mL). The combined organicextracts were washed with brine (80 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography 30% ethyl acetate gradient in hexane to affordIntermediate AA186-1 (1.3 g, 91.51%), MS (ES): m/z 227.05 [M+H]⁺

Step-2 synthesis ofN-((6-chloro-3-morpholinopyridin-2-yl)methyl)-N-ethylethanamine(Intermediate AA186)

To a solution of Intermediate AA186-1 (1.3 g, 5.75 mmol) in methanol (15mL) were added diethylamine (0.841 g, 11.5 mmol, 2.0 eq) and acetic acid(3.3 mL). After stirring at RT for 30 min, sodium cyanoborohydride(0.903 g, 14.37 mmol, 2.5 eq) was added in portions at 0° C. Afterstirring for 3 h at 60° C., the reaction mixture was concentrated underreduced pressure. The residue was purified by column chromatography(3.0% methanol gradient in DCM) to afford Intermediate AA186 (1.5 g,92.15%), MS (ES): m/z=284.1 [M+H]⁺

Synthesis of6-(3-(dimethylamino)azetidin-1-yl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA187)

Step-1 synthesis of tert-butyl(6-(3-(dimethylamino)azetidin-1-yl)-5-(furan-3-yl)pyridin-2-yl)carbamate(Intermediate AA187-1)

To a solution of Intermediate AA186-3 (0.350 g, 1.19 mmol) andN,N-dimethylazetidin-3-amine (0.32 g, 2.38 mmol, 1.2 eq) in 1,4-dioxane(4 mL) was added Cs₂CO₃ (1.1 g, 3.57 mmol, 2.0 eq). After degassingunder N2 stream for 15 min, Xantphos (0.068 g, 0.119 mmol, 0.1 eq) andPd₂(dba)₃ (0.1 g, 0.119 mmol, 0.1 eq) were added. After stirring at 100°C. for 5 h, the reaction mixture was cooled to RT, diluted water (50 mL)and extracted with ethyl acetate (3×30 mL). The combined organicextracts were washed with brine (90 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 45% ethyl acetate gradient in hexaneto afford Intermediate AA187-1 (0.440 g, 24.12%) as a brown solid. MS(ES): m/z=359.20 [M+H]⁺

Step-2 synthesis of tert-butyl(6-(3-(dimethylamino)azetidin-1-yl)-5-(THF-3-yl)pyridin-2-yl)carbamate(Intermediate AA187-2)

To a solution of Intermediate AA187-1 (0.440 g, 1.22 mmol) inmethanol:THF (6 mL:2 mL) were added Pd(OH)₂ (0.4 g), ammonium formate(0.3 g, 4.88 mmol, 4.0 eq) and acetic acid (0.4 mL). After stirringunder hydrogen gas at atmospheric pressure for 16 h at RT, the reactionmixture was filtered through celite-bed and washed with methanol. Thefiltrate was concentrated under reduced pressure. The residue wasneutralized with sodium bicarbonate solution and extracted with ethylacetate (3×30 mL). The combined organic layer was washed with brine (50mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography 2.5%methanol gradient in DCM to afford Intermediate AA187-7 (0.3 g, 67.42%).MS (ES): m/z 363.24 [M+H]⁺

Step-3 synthesis of6-(3-(dimethylamino)azetidin-1-yl)-5-(THF-3-yl)pyridin-2-amine(Intermediate AA187)

To a solution of Intermediate AA187-2 (0.3 g, 0.82 mmol) in DCM (3 mL)at 0° C. was added dropwise TFA (1 mL). After stirring at RT for 30 min,the reaction mixture was transferred into cold water, neutralized usingsaturated sodium bicarbonate solution, and extracted with DCM (3×20 mL).The combine organic layer was concentrated under reduced pressure toafford Intermediate AA187 (0.270 g, quantitative %). MS (ES): m/z 263.18[M+H]⁺

Synthesis of 5-cyclobutyl-6-((dimethylamino)methyl)pyridin-2-amine(Intermediate-AA188)

Step-1 Synthesis of tert-butyl(5-bromo-6-(hydroxymethyl)pyridin-2-yl)carbamate (Intermediate-AA188-1)

To a solution of Intermediate AA146-3 (50 g, 116.27 mmol) in ethanol(200 mL) was treated portion wise with sodium borohydride (26.3 g, 697.6mmol, 6 eq). After stirring at 70° C. for 2 h, the reaction mixture wasconcentrated under reduced pressure, quenched dropwise with water (200mL) and extracted into DCM (3×150 mL). The combined organic layer waswashed with brine (100 mL), passed through a hydrophobic filter, andconcentrated under reduced pressure to afford Intermediate-AA188-1 (27g, 79%), as white solid. MS (ES): m/z 395 [M+1]⁺ ¹H NMR (400 MHz, DMSO):δ 7.81 (d, 1H), 7.67 (d, 1H), 7.2 (d, 1H), 5.22 (d, 1H), 4.55 (t, 1H),3.99 (s, 3H), 3.77 (m, 3H), 3.55 (m, 2H), 2.28 (d, 2H), 1.87 (d, 1H),1.41 (s, 19H)

Step-2, 3 synthesis of tert-butyl(5-bromo-6-((dimethylamino)methyl)pyridin-2-yl)carbamate(Intermediate-AA188-2)

To a solution of the Intermediate-AA188-1 (22.2 g, 73.2 mmol) and N—Ndiisopropyl ethylamine (33.3 g, 256.3 mmol, 3.5 eq) in DCM (200 mL) at0° C. was added methane sulfonyl chloride (12.5 g, 109.8 mmol, 1.5 eq).After stirring for 30 min, the reaction was diluted with water (100 mL)and extracted with ethyl acetate (3×40 mL). The combined organic layerwas washed with brine, passed through a hydrophobic filter, andconcentrated under reduced pressure. To the residue dissolved inacetonitrile (200 mL) were added dimethyl amine (15 g, 183.0 mmol, 2.5eq) and N—N diisopropyl ethylamine (33.3 g, 256.3 mmol, 3.5 eq). Afterstirring at 70° C. for 1 h, the reaction was quenched with water (100mL) and extracted into ethyl acetate (3×40 mL). The combined organiclayer was washed with brine, passed through a hydrophobic filter, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with 50% ethyl acetate/hexane to affordIntermediate-AA188-2 (17.0 g, 94.3%). MS (ES): m/z 330 [M+H]⁺

Step-4 Synthesis of tert-butyl(6-((dimethylamino)methyl)-5-(1-hydroxycyclobutyl)pyridin-2-yl)carbamate(Intermediate-AA188-3)

To a solution of Intermediate-AA188-2 (1.0 g, 3.02 mmol) in THF (20 mL)at −78° C. was added n-BuLi (2.6 mL, 9.0 mmol,3 eq). After stirring at−78° C. for 1 h, cyclobutanone (0.420 g, 6.0 mmol, 2.0 eq) was addeddropwise. After complication of addition, the reaction mixture wasstirred at RT for 16 h. After complication the reaction, the reactionmixture was combined with four other batches at the same scale, quenchedwith NaHCO₃ and extracted with ethyl acetate (2×30 mL). The combinedorganic extracts were washed with brine (20 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography (2% methanol gradient in DCM) toafford Intermediate-AA188-3 (1.8 g, 29%). MS (ES): m/z=321.1 [M+1]⁺

Step-5 Synthesis of5-cyclobutyl-6-((dimethylamino)methyl)pyridin-2-amine (IntermediateAA188)

To a solution of Intermediate AA188-3 (1.3 g, 4.0 mmol) in DCE (15 mL)was added triethyl silane (6.5 mL, 40.85 mmol, 10 eq). After stirring atRT for 15 min, trifluoro acetic acid (6.5 mL, 5 vol) was added dropwiseat RT. After stirring at 60° C. for 1 h, the reaction mixture wasquenched with NaHCO₃ and extracted with ethyl acetate (2×30 mL). Thecombined organic extracts were washed with brine (20 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography (7% methanol gradient in DCM) andreversed phase prep HPLC purification to afford Intermediate-AA188 (175mg, 21%). MS (ES): m/z=206.2 [M+1]⁺

Synthesis of6-(((S)-3-methoxypyrrolidin-1-yl)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA189)

6-(((S)-3-methoxypyrrolidin-1-yl)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA189) was prepared from tert-butyl(6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate (IntermediateAA145-6) and (S)-3-methoxypyrrolidine in a similar fashion to thatprocedure of step-6, step-7 and step-8 described in synthesis of5-cyclopentyl-6-((dimethyl amino)methyl)pyridin-2-amine (IntermediateAA145) (1.2 g, quantitative %). m/z 278.1 [M+1-1]⁺

Synthesis of 6-amino-2-((dimethylamino)methyl)-N-ethylnicotinamide(Intermediate-AA190)

Step-1 Synthesis of methyl6-((tert-butoxycarbonyl)amino)-2-((dimethylamino)methyl)nicotinate(Intermediate AA190-4)

To a solution of Intermediate AA188-2 (2.0 g, 6.04 mmol,1.0 eq) in DCM(20 mL) was added triethylamine (2.5 mL, 18.12 mmol, 3.0 eq). Afterpurging carbon monoxide for 15 min,[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith DCM (2.5 mL, 0.5 mmol, 0.1 eq) was added. After stirring at 90° C.for 3 h, the reaction mixture was cooled to RT, diluted with water (100mL), and extracted into DCM (3×40 mL). The combined organic extractswere washed with brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by columnchromatography (2.5% methanol gradient in DCM) to afford IntermediateAA190-1 (1.2 g, 64.05%), MS (ES): m/z 310.1 [M+1]⁺

Step-2 Synthesis of tert-butyl(6-((dimethylamino)methyl)-5-(ethylcarbamoyl)pyridin-2-yl)carbamate(Intermediate AA190-2)

To a solution of Intermediate AA190-1 (1.1 g, 3.55 mmol) in toluene (11mL) were added dropwise ethylamine (0.48 g, 10.65 mmol, 3.0 eq) andtriazabicyclodecene (0.740 g, 5.32 mmol, 1.5 eq). After stirring at 110°C. for 4 h, the reaction was quenched with water (200 mL) and extractedinto ethyl acetate (3×80 mL). The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography (2% methanolgradient in DCM) to afford Intermediate AA190-2 (0.445 g, 38.82%). MS(ES): m/z=323.2 [M+H]⁺

Step-3 Synthesis of6-amino-2-((dimethylamino)methyl)-N-ethylnicotinamide (IntermediateAA190)

To a solution of Intermediate AA190-2 (0.445 g, 1.38 mmol) in DCM (5 mL)was added dropwise TFA (2 mL). After stirring at RT for 30 min, thereaction mixture was neutralized using sodium bicarbonate solution andextracted into DCM (3×20 mL). The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure to afford Intermediate AA190 (0.250 g, quantitative). MS (ES):m/z=223.1 [M+H]⁺

Synthesis of6-((dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine(Intermediate-AA191)

Step-1 Synthesis of tert-butyl(5-(3,6-dihydro-2H-pyran-4-yl)-6-((dimethylamino)methyl)pyridin-2-yl)carbamate(Intermediate AA191-1)

To a solution of Intermediate AA188-2 (50 g, 151.5 mmol) in1,4-dioxane:water (400 mL:100 mL) were add2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(47.7 g, 227.2 mmol, 1.5 eq) and potassium phosphate tribasic (96.3 g,454.5 mmol, 3.0 eq). After degassing with N2 for 15 min, X-phosPdG2(11.9 g, 15.1 mmol, 0.1 eq) was added. After stirring at 140° C. for 4h, the reaction mixture was cooled to RT, diluted with water (1 L), andextracted with ethyl acetate (2×2 L). The combined organic extracts werewash with brine (1 L), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by columnchromatography eluting with 2% methanol gradient in DCM to affordIntermediate AA191-1 (40 g, 79%), MS (ES): m/z 334.2 [M+H]⁺

Step-2 Synthesis of tert-butyl(6-((dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)carbamate(Intermediate AA191-2)

To a suspension of palladium hydroxide (130 g) in methanol (600 mL) andTHF (40 mL) was added Intermediate AA191-1 (130 g). After stirring underhydrogen gas at atmospheric pressure for 4 h at RT, the reaction mixturewas filtered through celite-bed and washed with methanol. The filtratewas concentrated under reduced pressure to afford Intermediate AA191-2(120 g, 91.75%). MS (ES): m/z 336.2 [M+H]⁺

Step-3 Synthesis of6-((dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine(Intermediate AA191)

To a solution of Intermediate AA191-2 (120 g, 356.9 mmol,1.0 eq) in DCM(1.2 L) was added TFA (360 mL) dropwise. After stirring at 55° C. for 2h, the reaction mixture was neutralized using saturated sodium hydroxidesolution and extracted with 10% methanol in DCM (4×10 L). The combineorganic layer was concentrated under reduced pressure to affordIntermediate AA191 (66 g, 78.40%). MS (ES): m/z 236.1 [M+H]⁺

Synthesis of6-((dimethylamino)methyl)-5-(3-methoxycyclopentyl)pyridin-2-amine(Intermediate-AA192)

Step-1 Synthesis of 3-bromocyclopent-2-en-1-one (Intermediate AA192-2)

To a solution of Intermediate AA192-1 (10 g, 10.19 mmol) in DCM (240 mL)was treated portion wise with triphenylphosphine (29.1 g, 11.11 mmol).After stirring at 0° C. for 30 mins, triethylamine (17 mL, 14.12 mmol,2.0 eq) and then bromine (5.7 mL, 11.11 mmol, 1.1 eq) were added. Afterstirring at RT for 20 min, the reaction was concentrated under reducedpressure, diluted with water (500 mL), and extracted by ethyl acetate.The combined organic layer was washed with brine, dried over Na₂SO₄, andconcentrated under reduced pressure. The residue was purified by columnchromatography (2% gradient of ethyl acetate in hexane) to affordIntermediate AA192-2 (10 g, 96.88%), MS (ES): m/z 303 [M+1]⁺

Step-2 Synthesis of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one(Intermediate AA192-3)

To a solution of Intermediate AA192-2 (1.5 g, 46.55 mmol) in dioxane (15mL) was added potassium acetate (2.6 g, 39.65 mmol, 4 eq) followed bydropwise addition of bispinacoline diborane (2.98 g, 40.55 mmol, 3.0eq). After degassing with argon for 10 mins, PdCl₂(dppf)₂(0.702 g,32.74mmol,0.07 eq) was added. After stirring at 120° C. for 30 mins, thereaction was quenched with water (500 mL) and extracted by ethylacetate. The combined organic layer was washed with brine, dried overNa₂SO₄, and concentrated under reduced pressure. The residue waspurified by column chromatography (10% gradient of ethyl acetate inhexane) to afford Intermediate AA192-3 (1.2 g, 96%), MS (ES): m/z299[M+1]+

Step-3 Synthesis of methyl6-(cyclopropanecarboxamido)-3-(3-oxocyclopent-1-en-1-yl)picolinate(Intermediate AA192-4)

To a solution of Intermediate AA149-1 (1 g, 12.94 mmol) in dioxane (15mL) was added potassium phosphate (2.2 g, 39.65 mmol, 3 eq) followed bydropwise addition of Intermediate AA192-3 (0.900 g, 40.55 mmol, 2.0 eq).After degassing with argon for 10 min, X-phose PdG2 (0.302 g, 32.74mmol, 0.05 eq) was added. After stirring at 80° C. for 1 h, the reactionwas diluted with water (500 mL) and extracted by ethyl acetate. Thecombined organic layer was washed with brine, dried over Na₂SO₄, andconcentrated under reduced pressure. The residue was purified by columnchromatography (12-15% gradient of ethyl acetate in hexane) to affordIntermediate AA192-4 (0.820 g, 95%), MS (ES): m/z 300[M+1]⁺

Step-4 synthesis of methyl6-(cyclopropanecarboxamido)-3-(3-hydroxycyclopent-1-en-1-yl)picolinate(Intermediate AA192-5)

To a solution of Intermediate AA192-4 (1 g, 33.89 mmol) in methanol (20mL) was treated portion wise with sodium borohydride (0.380 g, 16.9mmol, 3.0 eq) and followed by cesium chloride (0.5 mL). After stirringat rt for 1 h, the reaction was quenched with water (200 mL) andextracted into ethyl acetate (3×80 mL). The combined organic extractswere washed with brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by columnchromatography (20-30% gradient of ethyl acetate in hexane) to affordIntermediate AA192-5 (0.700 g, 100%). MS (ES): m/z=302 [M+H]⁺.

Step-5 synthesis of tert-butyl4-(6-(benzylamino)-3-(furan-3-yl)pyridin-2-yl)piperazine-1-carboxylate(Intermediate AA192-6)

To a solution of Intermediate AA192-5 (0.700 g, 12.70 mmol,1.0 eq) inTHF (20 mL) and methanol (3 mL) was added TMS-diazomethane complex(0.965 g, 12.70 mmol, 5.0 eq). After stirring at RT for 3 h, thereaction was diluted with sodium bicarbonate solution slowly andextracted into ethyl acetate. The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography (20%gradient of ethyl acetate in hexane) to afford Intermediate AA192-6(0.580 g, 98%), MS (ES): m/z 316 [M+1]⁺

Step-6 synthesis of methyl6-(cyclopropanecarboxamido)-3-(3-methoxycyclopentyl) picolinate(Intermediate AA192-7)

To a solution of Intermediate AA192-6 (0.580 g, 13.30 mmol) in THF (5.8mL) with acetic acid (0.4 mL) and ammonium formate (0.169 g, 26.7 mmol,2.0 eq) was added palladium hydroxide (1.0 g) in autoclave. Afterstirring at RT overnight with 20 psi hydrogen gas, the reaction mixturewas filtered through Celite bed. The filtrate was concentrated, and theresidue was purified by column chromatography (2% methanol gradient inDCM) to afford Intermediate AA192-7 (0.410 g, 94%). MS (ES): m/z=318[M+H]⁺

Step-7 Synthesis ofN-(6-(hydroxymethyl)-5-(3-methoxycyclopentyl)pyridin-2-yl)cyclopropanecarboxamide (Intermediate AA192-8)

To a solution of Intermediate AA192-7 (0.580 g, 37.27 mmol) in ethanol(7 mL) was treated portion wise with sodium borohydride (0.320 g, 23.62mmol, 6.0 eq). After stirring at 70° C. for 30 mins, the reaction wasconcentrated under reduced pressure, diluted with water (500 mL), andextracted with ethyl acetate. The combined organic layer was washed withbrine, dried over Na₂SO₄, and concentrated under reduced pressure. Theresidue was purified by column chromatography (2% gradient of ethylacetate in hexane) to afford Intermediate AA192-8 (0.400 g, 96.88%), MS(ES): m/z 290 [M+1]⁺

Step-8 & 9 synthesis ofN-(6-((dimethylamino)methyl)-5-(3-methoxycyclopentyl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA192-9)

To a solution of Intermediate AA192-8 (0.450 g, 37.02 mmol) in DCM (5mL) at 0° C. with diisopropylethylamine (0.240 g, 20.55 mmol, 1.5 eq wasadded mesyl chloride (0.530 g, 11.06 mmol, 3.0 eq). After stirring at 0°C. to RT for 15 mins, the reaction mixture was quenched with water (300mL) and extracted by DCM (2×100 mL). The combined organic layer waswashed with brine (100 mL), passed through a Na₂SO₄, and concentratedunder reduced pressure. (0.420 g, 74%), MS (ES): m/z 482 [M+1]⁺

To a solution of mesylated intermediate (0.420 g, 17.22 mmol) inacetonitrile (14 mL) was portion wise potassium carbonate (0.780 g,33.22 mmol, 6.0 eq) and dimethylamine.hydrochloride (0.362 g, 51.66mmol, 3.0 eq) dropwise. After stirring at 70° C. for 2 h., the reactionmixture was quenched with water (300 mL) and extracted by ethyl acetate.The combined organic layer was washed with brine (100 mL), passedthrough a Na₂SO₄, and concentrated under reduced pressure. The residuewas purified by column chromatography (5% methanol gradient in DCM) toafford Intermediate AA212-9 (0.290 g, 81.92%), MS (ES): m/z 317 [M+1]⁺

Step-10 Synthesis of6-((dimethylamino)methyl)-5-(3-methoxycyclopentyl)pyridin-2-amine(Intermediate AA192)

To a solution of Intermediate AA192-9 (0.290 g, 33.89 mmol) in methanol(5 mL) and water (1 mL) was treated portion wise with sodium hydride(0.320 g, 16.9 mmol, 3.0 eq) After stirring at rt for 1 h, the reactionwas quenched with water (200 mL) and extracted into ethyl acetate (3×80mL). The combined organic extracts were washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography (20-30% gradient elution ethylacetate in hexane) to afford Intermediate AA192 (0.120 g, 93%). MS (ES):m/z=249 [M+H]⁺.

Synthesis of4-(6-chloro-2-((dimethylamino)methyl)pyridin-3-yl)-1-methylpiperazin-2-one(Intermediate AA193)

Step-1 Synthesis of methyl6-chloro-3-(4-methyl-3-oxopiperazin-1-yl)picolinate(Intermediate-AA193-2)

To a solution of Intermediate-AA193-1(1.2 g, 6.36 mmol) in DMF (12.5 L)were added K₂CO₃ (2.6 g, 18.9 mmol, 3 eq) and 1-methylpiperazin-2-one(0.935 g, 6.8 mmol, 1.3 eq). After stirring at 80° C. for 12 h, thereaction mixture was quenched in water (100 mL) and extracted with ethylacetate (100 mL×3). The combined organic layer was dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by column chromatography to afford Intermediate-AA193-2. (0.815g, 47.33%). MS (ES): m/z 283.71 [M+H]⁺

Step-2 Synthesis of4-(6-chloro-2-(hydroxymethyl)pyridin-3-yl)-1-methylpiperazin-2-one(Intermediate-AA193-3)

To a solution of Intermediate-AA193-2 (0.700 g, 2.4 mmol) in ethanol (10mL) was treated portion wise with sodium borohydride (0.289 g, 12.04mmol, 5 eq). After stirring at 60° C. for 2 h, the reaction wasconcentrated under reduced pressure, quenched slowly with water (80 mL),and extracted by DCM (3×50 mL). The combined organic layer was washedwith brine (80 mL), passed through a Na₂SO₄, and concentrated underreduced pressure to afford Intermediate-AA193-3. (400 mg, 63.40%). MS(ES): m/z 256.70[M+1]⁺

Step-3 Synthesis of4-(6-chloro-2-((dimethylamino)methyl)pyridin-3-yl)-1-methylpiperazin-2-one(Intermediate AA193)

To a solution of Intermediate-AA193-3 (0.480 g, 1.8 mmol) in DCM (5 mL)with TEA (0.570 g, 56.4 mmol, 3.0 eq) at 0° C. was added mesyl chloride(0.429 g, 3.76 mmol, 2 eq). After stirring at RT for 2 h, the reactionmixture was quenched with water (70 mL) and extracted by DCM (3×30 ML).The combined organic layer was washed with brine (50 mL), passed througha Na₂SO₄, and concentrated under reduced pressure to afford mesylatedintermediate. (665 mg-crude).

To a solution of Mesylated above product (0.665 g, 1.99 mmol) inacetonitrile (6 mL) were added DIPEA (1.10 g, 8.5 mmol, 4.3 eq) anddimethylamine hydrochloride (0.501 g, 6.19 mmol, 3.1 eq) at RT. Afterstirring at 90° C. for 3 h, the reaction mixture was evaporated,quenched in water (70 mL), and extracted by DCM (3×30 mL). The combinedorganic layer was washed with brine (60 mL), dried with Na₂SO₄, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 1-5% MeOH in DCM to affordIntermediate-AA193. (0.370 g, quantitative yield). MS (ES): m/z 282.12[M+1]⁺

Synthesis of 6-((dimethylamino)methyl)-5-(methylsulfonyl)pyridin-2-amine(Intermediate AA194)

Step-1 Synthesis of4-(6-chloro-2-(hydroxymethyl)pyridin-3-yl)-1-methylpiperazin-2-one(Intermediate-AA194-1)

To a solution of Intermediate-AA154-2 (1 g) in THF (10 mL) was addedsodium methythionide (0.418 g, 5 eq). After stirring at 60° C. for 12 h,solvent evaporated under reduced pressure and purified by columnchromatography to afford thioether intermediate (400 mg).

To a solution of thioether intermediate (400 mg) in DCM (5 mL) was addedmCPBA (1 g, 5 eq). After stirring overnight. the solvent was removed,the residue was purified by column chromatography to affordIntermediate-AA194-1 (300 mg, 30%), MS (ES): m/z 250.67 [M+1]⁺.

Step-2 Synthesis of methyl6-(cyclopropanecarboxamido)-3-(methylsulfonyl)picolinate (IntermediateAA194-2)

To a solution of Intermediate AA194-1) (0.6 g) in 1,4-dioxane (8 mL)were added cyclopropyl carboxamide (0.3 g, 1.2 eq) and Cs₂CO₃ (0.71 g,3.0 eq). After degassing under N2 stream for 15 min, Xantphos (0.2 g,0.2 eq) and Pd₂(dba)₃ (0.157, 0.1 eq) were added. After stirring at 110°C. for 2 h, the reaction mixture was cooled to RT, diluted water (50 mL)and extracted with ethyl acetate (3×20 mL). The combined organicextracts were washed with brine (50 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography to afford Intermediate AA194-2 (0.4 g, 55%). MS(ES): m/z=299.31 [M+H]⁺

Step-3 Synthesis ofN-(6-(hydroxymethyl)-5-(methylsulfonyl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA194-3)

To a solution of Intermediate AA194-2 (1.5 g) in ethanol (15 mL) wastreated portion wise with sodium borohydride (6 eq). After stirring at60° C. for 2 h, the reaction was concentrated under reduced pressure,diluted slowly with water (100 mL), and extracted by DCM (4×50 mL). Thecombined organic layer was washed with brine (100 mL), passed through aNa₂SO₄, and concentrated under reduced pressure to afford IntermediateAA194-3 (800 g), MS (ES): m/z=270.31 [M+H]⁺

Step-4 & Step-5 Synthesis ofN-(6-((dimethylamino)methyl)-5-(methylsulfonyl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA194-4)

To a solution of Intermediate AA194-3 (1 g, 3.7 mmol) in DCM (15 mL)with diisopropylethylamine (1.8 mL, 11.11 mmol, 3.0 eq) at 0° C. wasadded mesyl chloride (0.446 g, 5.55 mmol, 1.5 eq). After stirring at RTfor 30 mins, the reaction mixture was quenched with water (300 mL) andextracted by DCM (2×100). The combined organic layer was washed withbrine (100 mL), passed through a Na₂SO₄, and concentrated under reducedpressure to afford mesylated intermediate (1 g), MS (ES): m/z 349 [M+1]⁺

To a solution of mesylated intermediate (1 g, 2.8 mmol) in acetonitrile(14 mL) was added dropwise diisopropylethylamine (1.2, 9.8 mmol, 3.5 eq)at RT. After heating to 100° C., Dimethylamine (0.4 g, 5.6 mmol, 2 eq)was added at 100° C. After stirring at same temperature for 2 h, thereaction mixture was cooled to RT, quenched with water (50 mL) andextracted by 10% methanol in DCM (2×500). The combined organic layer waswashed with brine (80 mL), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure to afford Intermediate AA194-4 (0.5 g), MS (ES):m/z 297.3 [M+1]⁺

Step-6 Synthesis of6-((dimethylamino)methyl)-5-(methylsulfonyl)pyridin-2-amine(Intermediate AA194)

To a solution of Intermediate AA194-4 (0.5 g, 1.6 mmol) inmethanol:water (20 mL:5 mL) was added sodium hydroxide (0.673 g, 16.8mmol, 10 eq). After stirring at RT for 16 h, the reaction mixture wasconcentrated under reduced pressure, diluted with water (30 mL),neutralized with 1N hydrochloric acid to pH-6.5 and extracted with DCM(3×30 mL). The combined organic layer was washed with brine solution,dried over sodium sulfate, and concentrated under reduced pressure toafford Intermediate AA194 (03 g, 64%). MS (ES): m/z 229.3 [M+H]⁺.

Synthesis of 6-((dimethylamino)methyl)-5-(THF-3-yl)pyrazin-2-amine(Intermediate-AA195)

Synthesis of 6-((dimethylamino)methyl)-5-(THF-3-yl)pyrazin-2-amine(Intermediate AA195) was prepared from methyl3-chloro-6-(cyclopropanecarboxamido)pyrazine-2-carboxylate (IntermediateAA195-2) in a similar fashion to that procedure describe in synthesis oftert-butyl ((6-amino-3-(THF-3-yl)pyridin-2-yl)methyl)carbamate(Intermediate AA149) (1.2 g, 87%). MS (ES) m/z 223.1 [M+H]⁺ andIntermediate AA195-2 was synthesized according to similar process ofIntermediate AA138-2.

Synthesis of 6-(4-methylpiperazin-1-yl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA196)

Step-1 synthesis ofN-(5-bromo-6-fluoropyridin-2-yl)cyclopropanecarboxamide (IntermediateAA196-2)

To a solution of Intermediate AA196-1 (5.0 g, 26.17 mmol) in DCM (50 mL)at 0° C. were added triethylamine (11.0 mL, 78.51 mmol, 3.0 eq) andcyclopropanecarbonyl chloride (10.8 g, 104.68 mmol, 4.0 eq). Afterstirring at RT for 2 h, the reaction mixture was diluted with water (150mL) and extracted with DCM (3×70 mL). The combined organic extracts werewashed with brine (200 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography (15-20% ethyl acetate gradient in hexane) to affordIntermediate AA196-2 (8.0 g, 95.84%) MS (ES): m/z=259.9 [M+H]⁺

Step-2 synthesis ofN-(6-fluoro-5-(furan-3-yl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA196-3)

To a solution of Intermediate AA196-2 (4.0 g, 15.44 mmol) in dioxane (86mL) and water (22 mL) were added furan-3-ylboronic acid (2.5 g, 23.16mmol, 1.5 eq) and potassium phosphate tribasic (8.1 g, 38.6 mmol, 2.5eq). After degassing with N2 for 15 min.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith DCM (1.2 g, 1.54 mmol, 0.1 eq) was added. After stirring at 100° C.for 2 h, the reaction mixture was cooled to RT, diluted water (300 mL)and extracted with ethyl acetate (2×150 mL). The combined organicextracts were washed with brine (200 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 34-37% ethyl acetate gradient inhexane to afford Intermediate AA196-3 (3.1 g, 81.54%), MS (ES): m/z247.08 [M+H]+

Step-3 synthesis ofN-(6-fluoro-5-(THF-3-yl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA196-4)

To a solution of Intermediate AA196-3 (3.1 g, 12.60 mmol) in methanol(30 mL) and THF (10 mL) were added ammonium formate (1.5 g, 25.2 mmol,2.0 eq), acetic acid (2.1 mL, 0.7V) and 20% wet palladium hydroxide oncarbon (2.5 g). After stirring under atmosphere of hydrogen gas for 24 hat RT, the reaction mixture was filtered through Celite bed, and thefiltrate was concentrated under reduced pressure. The residue wasdiluted with sat. NaHCO₃ solution and extracted by DCM. The organicsolution was concentrated to afford Intermediate AA196-4 (2.6 g,82.52%). MS (ES): m/z 251.1 [M+H]⁺

Step-4 Synthesis ofN-(6-(4-methylpiperazin-1-yl)-5-(THF-3-yl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA196-5)

To a cooled solution of Intermediate AA196-4 (2.5 g, 10.00 mmol) in THF(50 mL) was added dropwise n-butyllithium (1.6M in hexane) (12.5 mL, 20mmol, 2.0 eq) at 0° C. After stirring for 30 min at 0° C.1-methylpiperazine (2.0 g, 20 mmol, 2.0 eq) dissolved in THF (10 mL) wasadded. After stirring for 2 h at RT, the reaction mixture was quenchedwith water (150 mL) and extracted by ethyl acetate (2×60 mL). Thecombined organic layer was washed with brine (100 mL), passed through aNa₂SO₄, and concentrated under reduced pressure. The residue waspurified by column chromatography eluting 2.5% methanol gradient in DCMto afford Intermediate AA196-5 (1.5 g, 45.44%), MS (ES): m/z 331.2[M+H]⁺

Step-5 synthesis of6-(4-methylpiperazin-1-yl)-5-(THF-3-yl)pyridin-2-amine (IntermediateAA196)

To a solution of Intermediate AA196-5 (0.350 g, 4.54 mmol) in methanol(6 mL) and water (2 mL) was added sodium hydroxide (1.8 g, 45.4 mmol,10.0 eq). After stirring at 70° C. for 16 h, the reaction mixture wasdiluted with water (25 mL) and extracted with DCM (4×15 mL). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography eluting with 3% methanol gradient inDCM to afford Intermediate AA196 (0.9 g, 75.57%), m/z=263.1 [M+H]⁺

Synthesis of 3-(6-amino-2-((dimethylamino)methyl)pyridin-3-yl)THF-3-ol(Intermediate-AA197)

Step-1 synthesis of tert-butyl(6-((dimethylamino)methyl)-5-(3-hydroxyTHF-3-yl)pyridin-2-yl)carbamate(Intermediate AA197-1)

To a solution of Intermediate AA188-2 (7.0 g, 21.21 mmol) in THF (70 mL)was added n-butyl lithium at −78° C. After stirring for 1 h at −78° C.,dihydrofuran-3(2H)-one (3.64 g, 42.42 mmol, 2.0 eq) dissolved in THF (10mL) was added slowly dropwise. After stirring for 2 h at 78° C. warmingto RT, the reaction mixture was quenched with ice cold water (500 mL)and extracted with ethyl acetate (3×100 mL). The combined organicextracts were washed with brine (250 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 30% ethyl acetate gradient in hexaneto afford Intermediate AA197-1 (3.7 g, 51.73%), MS (ES): m/z 338.2[M+H]⁺

Step-2 Synthesis of3-(6-amino-2-((dimethylamino)methyl)pyridin-3-yl)THF-3-ol (IntermediateAA197)

The compound Intermediate AA197-1 (1.5 g, 4.45 mmol) in DCM (20 mL) wasadded trifluoroacetic acid (3 mL). After stirring at 50° C. for 2 h, thereaction mixture was quenched with saturated bicarbonate solution andextracted with DCM. The combined organic layer was dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by trituration with diethyl ether to afford IntermediateAA197 (0.75 g, 71.09%). MS (ES): m/z 238.1 [M+H]⁺

Synthesis ofR)-6-((dimethylamino)methyl)-5-((THF-3-yl)oxy)pyridin-2-amine(Intermediate-AA198)

Step-1 synthesis of S)-THF-3-yl 4-methylbenzenesulfonate (IntermediateAA198-2)

To a solution of the Intermediate AA198-1 (4.0 g, 45.45 mmol,1.0 eq) inDCM (40 mL) at 0° C. were added trimethylamine (6.3 mL, 45.45 mmol) andDMAP (1.6 g, 13.63 mmol,0.3 eq). After stirring for 10 min at 0° C.,4-toluenesulfonyl chloride (6.4 mL, 45.45 mmol) was added dropwise.After stirring for 30 min at RT and at 55° C. for 1 h, the reaction wasdiluted with 1N HCl (80 mL) and extracted into DCM (3×40 mL). Thecombined organic layer was washed with brine, filtered, and concentratedunder reduced pressure. The residue was purified by silica gelchromatography eluting with 30% ethyl acetate in hexane to affordIntermediate AA198-2 (3.5 g, 31.82%) as a yellow oil. MS (ES): m/z243.06 [M+H]⁺

Step-2 synthesis of methyl 6-bromo-3-hydroxypicolinate (IntermediateAA198-4)

To a solution of Intermediate AA198-3 (5.0 g, 32.67 mmol) in water (50mL) at 0° C. was added slowly dropwise bromine (2.0 mL, 39.20 mmol, 1.2eq). After stirring for 2 h, the reaction mixture was extracted with DCM(3×80 mL). The combined organic extracts were washed with brine (250mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure to afford Intermediate AA198-4 (4.0 g, 52.80%), MS (ES): m/z232.9 [M+H]⁺

Step-3 synthesis of methyl (R)-6-bromo-3-((THF-3-yl)oxy)picolinate(Intermediate AA198-5)

To a solution of Intermediate AA198-4 (4.0 g, 17.24 mmol) andIntermediate AA198-2 (5.4 g, 22.41 mmol, 1.5 eq) in DMF (20 mL) wasadded potassium carbonate (7.1 g, 51.72 mmol, 3.0 eq). After stirring at90° C. for 16 h, the reaction was diluted with ice cold water (250 mL)and extracted into ethyl acetate (3×80 mL). The combined organic layerwas washed with brine, filtered, and concentrated under reducedpressure. The residue was purified by silica gel chromatography elutingwith 17% ethyl acetate in hexane to afford Intermediate AA198-5 (3.5 g,67.20%) as a yellow oil. MS (ES): m/z 302.9[M+H]⁺

Step-4 synthesis of R)-(6-bromo-3-((THF-3-yl)oxy)pyridin-2-yl)methanol(Intermediate AA198-6)

To a solution of Intermediate AA198-5 (3.5 g, 11.58 mmol) in ethanol (35mL) was added portion wise sodium borohydride (0.717 g, 23.16 mmol, 2.0eq). After stirring at 60° C. for 30 min, the reaction was diluted withice cold water (200 mL) and extracted into ethyl acetate (3×60 mL). Thecombined organic layer was washed with brine, filtered, and concentratedunder reduced pressure. The residue was purified by silica gelchromatography eluting with 35% ethyl acetate in hexane to affordIntermediate AA198-6 (2.2 g, 69.28%). MS (ES): m/z 275.0[M+H]⁺

Step-5, 6 synthesis ofR)-1-(6-bromo-3-((THF-3-yl)oxy)pyridin-2-yl)-N,N-dimethylmethanamine(Intermediate AA198-7)

To a cooled solution of Intermediate AA198-6 (3.0 g, 10.98 mmol) in DCM(20 mL) with N, N-Diisopropylethylamine (6.7 mL, 38.43 mmol, 3.5 eq) at0° C. was added methane sulfonyl chloride (1.28 mL, 16.47 mmol, 1.5 eq)dropwise. After stirring at RT for 30 min, the reaction mixture wasdiluted with water (100 mL), washed with sodium bicarbonate solution,and extracted with DCM (3×30 mL). The combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure (1.61 g).

To a solution of mesylated intermediate (1.9 g, 5.39) in acetonitrile(20 mL) was added N,N-Diisopropylethylamine (2.8 mL, 16.17 mmol, 3.0 eq)and N-methylethanamine (2.1 g, 26.95 mmol, 5.0 eq) at RT. After stirring6 h at 90° C., the reaction mixture was diluted with ice cold water (150mL) and extracted with DCM (3×40 mL). The combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by silica gel chromatographyeluting with 4.5% methanol in DCM to afford Intermediate AA198-7 (1.8 g,74.46%) as a yellow oil. MS (ES): m/z 302.05 [M+H]⁺

Step-7 Synthesis ofR)—N-(6-((dimethylamino)methyl)-5-((THF-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA198-8)

To a solution of Intermediate AA198-7 (2.0 g, 6.64 mmol) in 1,4-dioxane(20 mL) were added cyclopropanecarboxamide (1.24 g, 14.61 mmol, 2.2 eq)and K₂CO₃ (2.74 g, 19.92 mmol, 3.0 eq). After degassing under N2 streamfor 15 min, Xantphos (0.383 g, 0.66 mmol, 0.1 eq) and Pd₂(dba)₃ (0.603g, 0.66 mmol, 0.1 eq) were added. After stirring at 100° C. for 2 h, thereaction mixture was cooled to RT, diluted with water (150 mL), andextracted with ethyl acetate (3×70 mL). The combined organic extractswere washed with brine (100 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 2-4% methanol gradient in DCM to affordIntermediate AA198-8 (1.8 g, 88.76%), m/z=306.18 [M+H]⁺

Step-8 synthesis ofR)-6-((dimethylamino)methyl)-5-((THF-3-yl)oxy)pyridin-2-amine(Intermediate AA198)

To a solution of Intermediate AA198-8 (1.8 g, 5.90 mmol) in methanol (20mL) and water (4 mL) was added sodium hydroxide (2.3 g, 59.0 mmol, 10.0eq). After stirring at 90° C. for 16 h, the reaction mixture was cooledto RT, concentrated under reduced pressure, diluted with water (100 mL),and extracted with DCM (3×40 mL). The combined organic extracts werewashed with brine (60 mL), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by trituration withhexane to afford Intermediate AA198 (0.9 g, 57.19%), MS (ES): m/z 238.1[M+H]⁺

Synthesis ofR)-1-((6-amino-3-((R)-THF-3-yl)pyridin-2-yl)methyl)pyrrolidin-3-ol(Intermediate-AA199)

(R)-1-((6-amino-3-((R)-THF-3-yl)pyridin-2-yl)methyl)pyrrolidin-3-ol(Intermediate-AA199) was prepared from tert-butyl(6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate (IntermediateAA145-6) and (R)-pyrrolidin-3-ol in a similar fashion to that procedureof step-6, step-7 and step-8 described in synthesis of5-cyclopentyl-6-((dimethylamino)methyl)pyridin-2-amine (IntermediateAA145) (0.8 g, quantitative %). m/z 264.1 [M+H]⁺

Synthesis of 6-((1-methylazetidin-3-yl)oxy)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA200)

Step-1 Synthesis of tert-butyl3-((3-bromo-6-chloropyridin-2-yl)oxy)azetidine-1-carboxylate(Intermediate AA200-2)

To a solution of Intermediate AA200-1 (15.0 g, 66.37 mmol) andtert-butyl 3-hydroxyazetidine-1-carboxylate (17.22 g, 99.55 mmol, 1.5eq) in acetonitrile (150 mL) was added cesium carbonate (43.1 g, 132.74mmol, 3.0 eq). After stirring at RT for 16 h, the reaction mixture wasdiluted with water (500 mL) and extracted with ethyl acetate (3×200 mL).The combined organic extracts were washed with brine (250 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography eluting with 1-3% gradientof ethyl acetate in hexane to afford Intermediate AA200-2 (14.0 g,58.23%), MS (ES): m/z 364.00 [M+H]⁺

Step-2 Synthesis of tert-butyl3-((6-chloro-3-(furan-3-yl)pyridin-2-yl)oxy)azetidine-1-carboxylate(Intermediate AA200-3)

A solution of Intermediate AA200-2 (14.0 g, 38.56 mmol) in1,4-Dioxane:water (140 mL:30 mL) were added furan-3-ylboronic acid (8.63g, 77.12 mmol, 2.0 eq) and sodium carbonate (8.1 g, 77.12 mmol, 2.0 eq).After degassing under N2 stream for 15 min[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith DCM (3.1 g, 3.85 mmol, 0.1 eq) was added. After stirring at 80° C.16 h, the reaction mixture was filtered through celite-bed. The filtratewas diluted with water (400 mL) and extracted with ethyl acetate (3×200mL). The combined organic extracts were washed with brine (250 mL),dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by column chromatography eluting with 30% ethylacetate gradient in hexane to afford Intermediate AA200-3 (9.0 g,66.64%) as a brown solid. MS (ES): m/z=351.1 [M+H]⁺

Step-3 synthesis of tert-butyl3-((6-(cyclopropanecarboxamido)-3-(furan-3-yl)pyridin-2-yl)oxy)azetidine-1-carboxylate(Intermediate AA200-4)

To a solution of Intermediate AA200-3 (9.0 g, 25.71 mmol) in 1,4-dioxane(90 mL) were added cyclopropanecarboxamide (4.37 g, 51.42 mmol, 2.0 eq)and K₂CO₃ (10.64 g, 77.13 mmol, 3.0 eq). After degassing under N2 streamfor 15 min, Xantphos (1.48 g, 2.57 mmol, 0.1 eq) and Pd₂(dba)₃ (2.3 g,2.57 mmol, 0.1 eq) were added. After stirring at 110° C. for 16 h, thereaction mixture was cooled to RT, diluted water (500 mL) and extractedwith ethyl acetate (3×200 mL). The combined organic extracts were washedwith brine (200 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with 25-30% ethyl acetate gradient in hexane to affordIntermediate AA200-4 (6.5 g, 63.43%), m/z=400.18 [M+H]⁺

Step-4 Synthesis of tert-butyl3-((6-amino-3-(furan-3-yl)pyridin-2-yl)oxy)azetidine-1-carboxylate(Intermediate AA200-5)

To a solution of Intermediate AA200-4 (6.5 g, 16.29 mmol) in methanol(70 mL) and water (20 mL) was added sodium hydroxide (6.51 g, 162.9mmol, 10.0 eq). After stirring at 80° C. for 16 h, the reaction mixturewas quenched with ice cold water, neutralized with 2N HCl solution, andextracted with ethyl acetate (3×100 mL). The combined organic extractswere washed with brine (150 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure The residue was purified by columnchromatography eluting with 20-30% ethyl acetate gradient in hexane toafford Intermediate AA200-5 (2.8 g, 51.93%), MS (ES): m/z 332.16 [M+H]⁺

Step-5 Synthesis of5-(furan-3-yl)-6-((1-methylazetidin-3-yl)oxy)pyridin-2-amine(Intermediate AA200-6)

To a cooled solution of Intermediate AA200-5 (2.8 g, 8.45 mmol) in THF(30 mL) at −10° C. was added lithium aluminum hydride (1.0 mL, 25.35mmol, 3.0 eq). After stirring at RT for 2 h, the reaction mixture wasquenched with ice cold water and ethyl acetate and filtered throughcelite-bed. The aqueous layer was extracted with ethyl acetate (3×80mL). The combined organic extracts were washed with brine (150 mL),dried over Na₂SO₄, filtered, and concentrated under reduced pressure Theresidue was purified by column chromatography eluting with 0-10%methanol gradient in DCM to afford Intermediate AA200-6 (1.2 g, 57.90%),MS (ES): m/z 246.1 [M+H]⁺

Step-6 Synthesis of6-((1-methylazetidin-3-yl)oxy)-5-(THF-3-yl)pyridin-2-amine (IntermediateAA200)

To a solution of Intermediate AA200-6 (1.2 g, 4.89 mmol) in methanol:THF(10 mL:2 mL) were added acetic acid (0.8 mL), palladium hydroxide oncarbon (0.6 g) and ammonium format (1.2 g, 19.56 mmol, 4.0 eq). Afterstirring under hydrogen gas at atmospheric pressure for 16 h at RT, thereaction mixture was filtered through celite-bed and washed withmethanol. The filtrate was concentrated under reduced pressure. Theresidue was purified by trituration with n-pentane to affordIntermediate AA200 (0.9 g, 73.79%). MS (ES): m/z 250.15 [M+H]⁺

Synthesis of 6-(1-(dimethylamino)ethyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate-AA201)

Step-1 Synthesis of 3-bromo-6-((tert-butoxycarbonyl)amino)picolinic acid(Intermediate AA201-1)

To a solution of Intermediate AA145-3 (20.0 g, 46.51 mmol) in THF:methanol:water (200 mL:200 mL:30 mL) was added sodium hydroxide (9.3 g,232.55 mmol, 5.0 eq). After stirring at RT for 16 h, the reactionmixture was concentrated under reduced pressure. The residue wasneutralized with citric acid solution whereby a solid precipitate fromsolution. The solid was filtered and dried under high vacuum to affordIntermediate AA201-1 (13.6 g, 70.29%), MS (ES): m/z 418.06 [M+H]⁺

Step-2 Synthesis of tert-butyl(5-bromo-6-(methoxy(methyl)carbamoyl)pyridin-2-yl)carbamate(Intermediate AA201-2)

To a solution of Intermediate AA201-1 (5.0 g, 11.96 mmol) in DMF (50 mL)were added N,O-dimethylhydroxylamine hydrochloride (1.4 g, 14.35 mmol,1.2 eq), hydroxybenzotriazole (2.4 g, 17. 94 mmol, 1.5 eq),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.7 g, 29.9mmol, 2.5 eq) and triethylamine (5.0 mL, 35.88 mmol, 3.0 eq). Afterstirring at RT for 8 h, the reaction mixture was transferred into water(200 mL) and extracted with ethyl acetate (3×60 mL). The combinedorganic layer was washed with brine solution, dried over sodium sulfate,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 20% ethyl acetate in hexane to affordIntermediate AA201-2 (4.6 g, 83.39%). MS (ES): m/z 461.1 [M+H]⁺

Step-3 Synthesis of tert-butyl (6-acetyl-5-bromopyridin-2-yl)carbamate(Intermediate AA201-3)

To a solution of Intermediate AA201-2 (4.6 g, 10.00 mmol) in THF (50mL)) at 0° C. was added dropwise 3M methyl magnesium bromide solution(1.48 g, 2.57 mmol, 0.1 eq). After stirring at RT for 6 h, the reactionmixture was diluted with sodium bicarbonate solution (80 mL), extractedwith ethyl acetate (3×30 mL) and filtered through celite-bed. Thecombined organic extracts were concentrated under reduced pressure. Theresidue was purified by column chromatography eluting with 20-25% ethylacetate gradient in hexane to afford Intermediate AA201-3 (3.1 g,98.43%), m/z=316.02 [M+H]⁺

Step-4 Synthesis of tert-butyl(5-bromo-6-(1-(dimethylamino)ethyl)pyridin-2-yl)carbamate (IntermediateAA201-4)

To a solution of Intermediate AA201-3 (2.8 g, 9.84 mmol) in methanol (30mL) were added acetic acid (2.8 mL) and dimethylamine solution (2M inTHF). After stirring at RT for 1 h, sodium cyanoborohydride (3.0 g, 49.2mmol, 5.0 eq) was added portion wise. After stirring at 70° C. for 2 h,the reaction mixture was diluted with water (100 mL) and extracted withethyl acetate (3×70 mL). The combined organic extracts were washed withbrine (150 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure The residue was purified by column chromatographyeluting with 1-5% methanol gradient in DCM to afford IntermediateAA201-4 (1.9 g, 56.11%), MS (ES): m/z 345.09[M+H]⁺

Step-5 Synthesis of tert-butyl(6-(1-(dimethylamino)ethyl)-5-(furan-3-yl)pyridin-2-yl)carbamate(Intermediate AA201-5)

To a solution of Intermediate AA201-4 (1.9 g, 5.53 mmol) andfuran-3-ylboronic acid (0.93 g, 8.29 mmol, 1.5 eq) in 1,4-dioxane:water(20 mL:4 mL) was added potassium phosphate tribasic (3.5 g, 16.59 mmol,3.0 eq). After degassing under N2 stream for 15 min, Xphose PdG2 (0.434g, 0.55 mmol, 0.1 eq) was added. After stirring at 120° C. for 20 min,the reaction mixture was diluted with water (50 mL) and extracted withethyl acetate (3×25 mL). The combined organic extracts were washed withbrine (80 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure The residue was purified by column chromatographyeluting with 3% methanol gradient in DCM to afford Intermediate AA201-5(1.1 g, 60.14%), MS (ES): m/z 332.1 [M+H]⁺

Step-6 Synthesis of tert-butyl(6-(1-(dimethylamino)ethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate(Intermediate AA201-6)

To a solution of Intermediate AA201-5 (1.1 g, 3.32 mmol) in methanol:THF(10 mL:2 mL) were added acetic acid (0.8 mL), palladium hydroxide oncarbon (0.6 g) and ammonium format (1.2 g, 19.92 mmol, 6.0 eq). Afterstirring under hydrogen gas at atmospheric pressure for 16 h at RT, thereaction mixture was filtered through celite-bed and washed withmethanol. The filtrate was concentrated under reduced pressure. Theresidue was purified by trituration with n-pentane to affordIntermediate AA201-6 (1.0 g, 89.82%). MS (ES): m/z 336.22 [M+H]⁺

Step-7 Synthesis of6-(1-(dimethylamino)ethyl)-5-(THF-3-yl)pyridin-2-amine (IntermediateAA201)

To a solution compound Intermediate AA201-6 (1.5 g, 2.98 mmol) in DCM(15 mL) was added trifluoroacetic acid (4 mL). After stirring at RT for1 h, the reaction mixture concentrated under reduced pressure. Theresidue was diluted with water (30 mL) and DCM (15 mL). The aqueouslayer was collected, neutralized by 1N NaOH solution and extracted with10% methanol in DCM (3×25 mL). The combined organic extracts were washedwith brine (40 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure to afford Intermediate AA201 (0.560 g, 79.82%). MS(ES): m/z 236.1 [M+H]⁺

Synthesis of4-(6-chloro-2-((dimethylamino)methyl)pyridin-3-yl)-1,4-oxazepan-6-ol(Intermediate-AA202)

Step-1 Synthesis of methyl 6-chloro-3-fluoropicolinate (IntermediateAA202-1)

To a solution of Intermediate AA202-1 (4.0 g, 22.85 mmol) in DMF (40 mL)with potassium carbonate (15.7 g, 114.25 mmol, 5.0 eq) at 0° C. wasadded methyl iodide (4.2 mL, 68.55 mmol, 3.0 eq) dropwise. Afterstirring from 0-RT for 1 h, the reaction mixture was diluted with water(250 mL) and extracted with ethyl acetate (3×80 mL). The combinedorganic extracts were washed with brine (120 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure to afford IntermediateAA202-1 (2.58 g, 59.73%), MS (ES): m/z 190.0 [M+H]⁺

Step-2 Synthesis of methyl6-chloro-3-(6-hydroxy-1,4-oxazepan-4-yl)picolinate (IntermediateAA202-2)

To a solution of Intermediate AA202-1 (2.5 g, 13.22 mmol) and1,4-oxazepan-6-ol (3.0 g, 26.45 mmol, 2.0 eq) in DMF (25 mL) was addedN, N-Diisopropylethylamine (11.5 mL, 66.1 mmol, 5.0 eq). After stirringat 80° C. for 16 h, the reaction mixture was cooled to RT, diluted withice cold water (80 mL) and extracted with ethyl acetate (3×30 mL). Thecombined organic extracts were washed with brine (60 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography eluting with 40-45% ethyl acetategradient in hexane to afford Intermediate AA202-2 (1.5 g, 39.67%), MS(ES): m/z 287.08 [M+H]⁺

Step-3 Synthesis of methyl3-(6-(benzyloxy)-1,4-oxazepan-4-yl)-6-chloropicolinate (IntermediateAA202-4)

To a solution of Intermediate AA202-2 (0.9 g, 3.14 mmol) in DMF (10 mL)at 0° C. was added portion wise 60% sodium hydride (0.376 g, 9.42 mmol,3.0 eq). After stirring for 30 min at 0° C., benzyl bromide (0.5 mL,4.71 mmol, 1.5 eq) was added dropwise. After stirring for 1 h, thereaction mixture was quenched with ice cold water (30 mL) and extractedwith ethyl acetate (3×30 mL). The combined organic extracts were washedwith brine (60 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with 2% methanol gradient in DCM to afford Intermediate AA202-4(0.750 g, 63.40%), m/z=377.1 [M+H]⁺

Step-4 Synthesis of3-(6-(benzyloxy)-1,4-oxazepan-4-yl)-6-chloropyridin-2-yl)methanol(Intermediate AA202-5)

To a solution of Intermediate AA202-4 (0.750 g, 1.99 mmol) in ethanol (8mL) at 0° C. was added portion wise sodium borohydride (0.376 g, 9.95mmol, 5.0 eq). After stirring at RT for 2 h, the reaction was dilutedwith ice cold water (80 mL) and extracted into ethyl acetate (3×30 mL).The combined organic layer was washed with brine, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography eluting with 20% ethyl acetatein hexane to afford Intermediate AA202-5 (0.5 g, 72.02%). MS (ES): m/z349.13[M+H]⁺

Step-5,6 Synthesis of1-(3-(6-(benzyloxy)-1,4-oxazepan-4-yl)-6-chloropyridin-2-yl)-N,N-dimethylmethanamine(Intermediate AA202)

To a solution of Intermediate AA202-5 (0.5 g, 1.43 mmol) in DCM at 0° C.(5 mL) with triethylamine (1.0 mL, 7.15 mmol, 5.0 eq) was added methanesulfonyl chloride (0.33 mL, 4.29 mmol, 3.0 eq) dropwise. After stirringat RT for 30 min, the reaction mixture was diluted with water (50 mL),washed with sodium bicarbonate solution, and extracted with DCM (3×20mL). The combined organic extracts were washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure to affordmesylate intermediate (0.39 g).

To the mesylate intermediate (0.39 g, 0.91 mmol) in acetonitrile (5 mL)were added N,N-diisopropylethylamine (1.56 mL, 9.1 mmol, 10 eq) andN-methylethanamine (0.773 g, 9.1 mmol, 10.0 eq) at RT. After stirringfor 6 h at 90° C., the reaction mixture was diluted with ice cold water(150 mL) and extracted with DCM (3×40 mL) The combined organic extractswere washed with brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by silica gelchromatography eluting with 4.5% methanol in DCM to afford IntermediateAA202 (1.8 g, 63.10%). MS (ES): m/z 376.17 [M+H]⁺

Synthesis of1-(6-chloro-3-(1-methoxycyclopropyl)pyridin-2-yl)-N,N-dimethylmethanamine(Intermediate AA203)

Intermediate-AA203-1 was synthesize using the procedure ofWO2008/110611.

Step-1 Synthesis of 2-chloro-5-(1-methoxycyclopropyl)pyridine(Intermediate-AA203-2)

To a solution of Intermediate-AA203-1 (1.5 g, 3.09 mmol, 1 eq) in THF at0° C. was added NaH (0.123 g, 6.1 mmol, 2 eq). After stirring at RT for15 min, MeI (0.5 g, 4.6 mmol, 1.5 eq) was added. After stirring for 2 h,the reaction was diluted ethyl acetate (70 mL) and water (20 mL). Theorganic layer was collected, and the aqueous phase was extract withethyl acetate (2×30 mL). The combined organic extracts were washed withbrine (50 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure to afford Intermediate-AA203-1 (1.2 g, 73.5%). MS (ES):m/z=183.64 [M+1]+.

Step-2 Synthesis of 2-chloro-5-(1-methoxycyclopropyl)pyridine 1-oxide(Intermediate-AA203-3) and Step-3 Synthesis of1-(6-chloro-3-(1-methoxycyclopropyl)pyridin-2-yl)-N,N-dimethylmethanamine(Intermediate-AA203)

2-chloro-5-(1-methoxycyclopropyl)pyridine 1-oxide (Intermediate-AA203-3)and1-(6-chloro-3-(1-methoxycyclopropyl)pyridin-2-yl)-N,N-dimethylmethanamine(Intermediate AA202) were prepared from Intermediate AA203-2 in asimilar fashion to that procedure of step-4, step-5 described insynthesis of6-chloro-3-(4-(methoxymethyl)tetrahydro-2H-pyran-4-yl)picolinonitrile(Intermediate AA208) (150 mg, 33% overall two step). MS (ES): m/z=241.73(M+H)+.

Synthesis of4-(6-chloro-2-((dimethylamino)methyl)pyridin-3-yl)tetrahydro-2H-pyran-4-carbonitrile(Intermediate AA204)

Intermediate-AA204-1 was synthesized using the procedure ofWO2015/94912, 2015, A1

Step-1 Synthesis of methyl6-chloro-3-(4-cyanotetrahydro-2H-pyran-4-yl)picolinate(Intermediate-AA204-2)

To a solution of Intermediate-AA204-1) (1 g, 4.7 mmol, 1 eq), in THF (10mL) at 0° C. was added NAH (0.571 g, 14.2 mmol, 3 eq). After stirring at0° C. for 30 min, 1-bromo-2-(2-bromoethoxy)ethane (2.15 g, 9.4 mmol, 2eq) was added. After stirring at RT for 1 h, the reaction mixture wasdiluted with water (50 mL) and extracted with ethyl acetate (50 mL). Thecombined organic extracts were washed with brine (60 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography to afford Intermediate-AA204-2(600 mg, 45%). MS (ES): m/z=280.71 [M+1]+

Step-2 Synthesis of4-(6-chloro-2-(hydroxymethyl)pyridin-3-yl)tetrahydro-2H-pyran-4-carbonitrile(Intermediate-AA204-3)

To a solution of Intermediate-AA204-2 (1.5 g, 5.3 mmol, 1 eq) in EtOH(20 mL) at 0° C. was added NaBH4 (0.5 g, 10.6 mmol, 2 eq). Afterstirring at RT for 2 h, the reaction was concentrated, diluted withwater (50 mL), and extracted with ethyl acetate (3×40 mL). The combinedorganic extracts were wash with brine (50 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure to affordIntermediate-AA204-2. (1.1 g, 81%) MS (ES): m/z=253.5 [M+H]⁺

Step-3 & Step-4 Synthesis of4-(6-chloro-2-((dimethylamino)methyl)pyridin-3-yl)tetrahydro-2H-pyran-4-carbonitrile(Intermediate-AA204)

To a solution of Intermediate-AA204-2 (1 g, 4.7, 1 eq) in DCM (10 mL) at0° C. were added DIPEA (2.12 g, 16.45 mmol, 3.5 eq) and methane sulfonylchloride (0.4 g, 7.05 mmol, 1.5 eq). After stirring at 0° C. for 30 min,the reaction mixture was diluted with water (50 mL) and extracted withethyl acetate (3×40 mL). The combined organic extracts were wash withbrine (50 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure to afford mesylate intermediate (1.2 g) MS (ES):m/z=331.5 [M+H]⁺.

To a solution of mesylated intermediate (1.2 g, 3.6 mmol) in MeCN (12mL) was added dropwise DIPEA (2.1 g, 16.3 mmol, 4.5 eq) anddimethylamine hydrochloride (0.8 g, 7.2 mmol, 2.0 eq) at RT. Afterstirring at 90° C. for 3 h, the reaction mixture was concentrated,quenched in water (55 mL), and extracted by DCM (3×30 L). The combinedorganic layer was washed with brine (80 mL), dried with Na₂SO₄, andconcentrated under reduced pressure to afford Intermediate-AA204 (600mg, quantitative yield), as brown semisolid. MS (ES): m/z 280.39 [M+H]⁺.

Synthesis of(2R)-1-((6-amino-3-(THF-3-yl)pyridin-2-yl)methyl)pyrrolidin-2-yl)methanol(Intermediate-AA205)

((2R)-1-((6-amino-3-(THF-3-yl)pyridin-2-yl)methyl)pyrrolidin-2-yl)methanol(Intermediate-AA205) was prepared from tert-butyl(6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate (IntermediateAA145-6) and (R)-pyrrolidin-2-ylmethanol in a similar fashion to thatprocedure of step-6, step-7 and step-8 described in synthesis of5-cyclopentyl-6-((dimethylamino)methyl)pyridin-2-amine (IntermediateAA145) (0.85 g, quantitative %). m/z 278.1[M+H]⁺

Synthesis of(2S)-1-((6-amino-3-(THF-3-yl)pyridin-2-yl)methyl)pyrrolidin-2-yl)methanol(Intermediate-AA206)

((2S)-1-((6-amino-3-(THF-3-yl)pyridin-2-yl)methyl)pyrrolidin-2-yl)methanol(Intermediate-AA206) was prepared from tert-butyl(6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate (IntermediateAA145-6) and (S)-pyrrolidin-2-ylmethanol in a similar fashion to thatprocedure of step-6, step-7 and step-8 described in synthesis of5-cyclopentyl-6-((dimethylamino)methyl)pyridin-2-amine (IntermediateAA145) (0.85 g, quantitative %). m/z 278.1 [M+H]⁺

Synthesis of1-(6-chloro-3-(4-methoxytetrahydro-2H-pyran-4-yl)pyridin-2-yl)-N,N-dimethylmethanamine(Intermediate-AA207)

Step-1 synthesis of1-(6-chloro-3-(4-methoxytetrahydro-2H-pyran-4-yl)pyridin-2-yl)-N,N-dimethylmethanamine(Intermediate AA207)

To a solution of Intermediate AA154 (0.5 g, 1.85 mmol) in THF (5 mL) at0° C. was added sodium hydride (60%) (0.22 g, 5.55 mmol, 3.0 eq) andthen methyl iodide (0.315 g, 2.22 mmol, 1.2 eq). After stirring at RTfor 2 h, the reaction mixture was diluted with cold water (30 mL) andextracted with ethyl acetate (3×20 mL). The combined organic extractswere washed with brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure to afford Intermediate AA207 (0.220 g, 41.83%) MS(ES): m/z=285.1 [M+H]⁺

Synthesis of6-chloro-3-(4-(methoxymethyl)tetrahydro-2H-pyran-4-yl)picolinonitrile(Intermediate-AA208)

Step-1 Synthesis of methyl4-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-4-carboxylate (IntermediateAA208-1)

To a solution of the Intermediate AA150-2 (3 g, 16.21 mmol) in DMF (30mL) at 0° C. was added sodium hydride (1.6 g, 40.52 mmol, 2.5 eq). After15 min, 1-bromo-2-(2-bromoethoxy) ethane (7.5 g, 32.42 mmol, 2.0 eq) wasadded. After stirring at RT for 1 h, the reaction mixture was quenchedin ice cold water (100 mL) and extracted with ethyl acetate (3×30 mL).The combined organic extracts were washed with brine (90 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure to affordIntermediate AA208-2 (2.1 g, 50.81%) MS (ES): m/z 256.07[M+H]⁺

Step-2 Synthesis of4-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-4-yl)methanol (IntermediateAA208-2)

To a solution of Intermediate AA208-1 (2.1 g, 8.23 mmol) in methanol(100 mL) at 0° C. was added portion wise sodium borohydride (1.8 g,49.38 mmol, 6.0 eq). After stirring at RT for 1 h, the reaction mixturewas concentrated under reduced pressure and extracted with ethyl acetate(80 mL). The organic layer was concentrated under reduced pressure toafford Intermediate AA208-2 (1.5 g, 80.22%) MS (ES): m/z 228.07 [M+H]⁺

Step-3 Synthesis of2-chloro-5-(4-(methoxymethyl)tetrahydro-2H-pyran-4-yl)pyridine(Intermediate AA208-3)

To a cooled solution of Intermediate AA208-2 (0.5 g, 2.20 mmol) in DMF(5 mL) at 0° C. was added sodium hydride (0.220 g, 5.5 mmol, 2.5 eq).After 15 min methyl iodide (0.27 mL, 4.4 mmol, 2.0 eq) was added. Afterstirring at RT for 1 h, the reaction mixture was quenched in ice coldwater (50 mL) and extracted with ethyl acetate (3×15 mL). The combinedorganic extracts were washed with brine (40 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure to afford IntermediateAA208-3 (0.450 g, 84.78%) MS (ES): m/z 242.09 [M+H]⁺

Step-4 Synthesis of2-chloro-5-(4-(methoxymethyl)tetrahydro-2H-pyran-4-yl)pyridine 1-oxide(Intermediate AA208-4)

To a solution of the Intermediate AA208-4 (0.485 g, 1.86 mmol) in DCM (5mL) at 0° C. was added urea H₂O₂ (0.524 g, 5.58 mmol, 3.0 eq, cas no:124-43-6). After stirring for 15 min at 01C, trifluoroacetic anhydride(1.1 g, 5.58 mmol, 3.0 eq) was added at 0° C. After stirring at RT for 1h, the reaction mixture was quenched in water (60 mL) and extracted withDCM (3×20 mL). The combined organic extracts were washed with brine (50mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography eluting with2% elution methanol in DCM to afford Intermediate AA208-4 (0.420 g,87.54%) MS (ES): m/z 258.09 [M+H]⁺

Step-5 Synthesis of6-chloro-3-(4-(methoxymethyl)tetrahydro-2H-pyran-4-yl)picolinonitrile(Intermediate AA208)

To a solution of Intermediate AA208-4 (0.420 g, 1.63 mmol) inacetonitrile (5 mL) were added trimethylamine (0.6 mLg, 4.89 mmol, 3.0eq) and trimethylsilyl cyanide (0.6 mL, 4.89 mmol, 3.0 eq). Afterstirring at 120° C. for 16 h, the reaction mixture was quenched in water(50 mL) and extracted with ethyl acetate (3×20 mL). The combined organicextracts were washed with brine (40 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 1% elution methanol in DCM to affordIntermediate AA208 (0.250 g, 57.51%) MS (ES): m/z 267.02 [M+H]⁺

Synthesis ofN-(2-(6-amino-3-(THF-3-yl)pyridin-2-yl)propan-2-yl)acetamide(Intermediate-AA209)

Step-1 synthesis of 2-(3-bromo-6-chloropyridin-2-yl)propan-2-ol(Intermediate AA209-2)

To a solution of Intermediate AA154-2 (10 g, 40.32 mmol) in THF (100 mL)at 0° C. was added dropwise methyl magnesium bromide solution (3.0M indiethyl ether) (100 mL). After stirring at 0° C. for 1 h and for 15 minat RT, the reaction mixture was quenched in water (500 mL) and extractedwith ethyl acetate (3×100 mL). The combined organic extracts were washedwith brine (200 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure to afford Intermediate AA209-2 (7.0 g, quantitative %)which was used in the next step without further purification. MS (ES):m/z 250.9 [M+H]⁺

Step-2 synthesis ofN-(2-(3-bromo-6-chloropyridin-2-yl)propan-2-yl)acetamide (IntermediateAA209-3)

To a solution of sulfuric acid (100 mL) in acetonitrile (25 mL) at 0° C.was added dropwise in solution of Intermediate AA209-2 (5.5 g, 22.00mmol) in acetonitrile (60 mL). After stirring at 55° C. for 4 h, thereaction mixture was quenched in ice cold water and sodium bicarbonatesolution and extracted with ethyl acetate (3×100 mL). The combinedorganic extracts were washed with brine, dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 30% elution ethyl acetate in hexaneto afford Intermediate AA209-3 (2.5 g, 39.05%) MS (ES): m/z=291.1 [M+H]⁺

Step-3 Synthesis ofN-(6-(2-acetamidopropan-2-yl)-5-bromopyridin-2-yl)cyclopropanecarboxamide(Intermediate AA209-4)

To a solution of Intermediate AA209-3 (3.6 g, 12.37 mmol) andcyclopropanecarboxamide (3.1 g, 37.11 mmol, 3.0 eq) in 1,4-dioxane (36mL) was added K₂CO₃ (5.1 g, 37.11 mmol, 3.0 eq). After degassing underN2 stream for 15 min, Xantphos (1.4 g, 2.47 mmol, 0.2 eq) and Pd₂(dba)₃(1.1 g, 1.23 mmol, 0.1 eq) were added. After stirring at 100° C. for 5h, the reaction mixture was cooled to RT, diluted water (150 mL) andextracted with ethyl acetate (3×60 mL). The combined organic extractswere washed with brine (70 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 40-45% ethyl acetate gradient in hexane toafford Intermediate AA209-4 (2.5 g, 59.51%), m/z=341.06 [M+2]⁺

Step-4 synthesis ofN-(6-(2-acetamidopropan-2-yl)-5-(furan-3-yl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA209-5)

To a solution of Intermediate AA209-4 (2.5 g, 7.30 mmol) in1,4-dioxane:water (25 mL:5 mL) were added furan-3-ylboronic acid (2.0 g,18.27 mmol, 2.5 eq), and potassium phosphate tribasic (4.64 g, 21.9mmol, 3.0 eq). After degassing with N2 for 15 min, X-Phos pd G2 (0.573g, 0.73 mmol, 0.1 eq) was added. After stirring at 100° C. for 1 h, thereaction mixture was diluted with water (120 mL) and extracted withethyl acetate (2×50 mL). The combined organic extracts were washed withbrine (130 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with 40-45% ethyl acetate gradient in hexane to affordIntermediate AA209-5 (1.7 g, 70.67%), MS (ES): m/z 328.1 [M+H]⁺

Step-5 Synthesis ofN-(6-(2-acetamidopropan-2-yl)-5-(THF-3-yl)pyridin-2-yl)cyclopropanecarboxamide(Intermediate AA209-6)

To a solution of Intermediate AA209-5 (0.9 g, 2.75 mmol) in methanol (10mL) was added Rhodium on alumina (0.9 g). After stirring at RT for 16 h,the reaction mixture was filtered through celite-bed and washed with 10%methanol in DCM. The filtrate was concentrated under reduced pressure.The residue was purified by column chromatography eluting with 60% ethylacetate gradient in hexane to afford Intermediate AA209-6 (0.6 g,65.86%), m/z=332.1 [M+H]⁺

Step-6 Synthesis ofN-(2-(6-amino-3-(THF-3-yl)pyridin-2-yl)propan-2-yl)acetamide(Intermediate AA209)

To a solution of Intermediate AA209-6 (0.6 g, 1.81 mmol) in methanol (8mL) and water (2 mL) was added sodium hydroxide (0.868 g, 21.72 mmol,12.0 eq). After stirring at 80° C. for 16 h, the reaction mixture wasdiluted with water (30 mL) and extracted with DCM (4×15 mL). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure to afford IntermediateAA209 (0.400 g, 83.90%), MS (ES) m/z=264.1 [M+H]⁺

Synthesis of1-(6-chloro-3-(4-fluorotetrahydro-2H-pyran-4-yl)pyridin-2-yl)-N,N-dimethylmethanamine(Intermediate-AA210)

Step-1 Synthesis of1-(6-chloro-3-(4-fluorotetrahydro-2H-pyran-4-yl)pyridin-2-yl)-N,N-dimethylmethanamine(Intermediate AA210)

To a solution of Intermediate AA154 (0.250 g, 0.92 mmol) in DCM (5 mL)at −15° C. was added dropwise diethylaminosulfur trifluoride (0.296 g,1.84 mmol, 2.0 eq) diluted in DCM. After stirring at −15° C. for 15 min,the reaction mixture was diluted with cold water (30 mL), quenched bysodium bicarbonate solution and extracted with DCM (3×20 mL). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure to afford IntermediateAA210 (0.150 g, 59.56%) MS (ES): m/z=273.1 [M+H]⁺

Synthesis of1-(6-bromo-3-(2,2-difluoroethoxy)pyridin-2-yl)-N,N-dimethylmethanamine(Intermediate-AA211)

Step-1 Synthesis of 2,2-difluoroethyl4-methylbenzenesulfonatemethyl6-bromo-3-(2,2-difluoroethoxy)picolinate(Intermediate AA211-2)

To a solution of Intermediate AA211-1 (3.1 g, 37.80 mmol) in DCM (30 mL)were added triethylamine (3.81 g/5.2 ml, 37.80 mmol, 1 eq) dropwise,DMAP (1.38 g, 11.3 mmol, 0.3 eq) and tosyl chloride (7.18 g, 37.80 mmol,1 eq) at RT. After stirring at 60° C. and for 1 h, the reaction mixturewas quenched with water (300 mL) and extracted by EtOAc (2×100). Thecombined organic layer was washed with brine (100 mL), passed through aNa₂SO₄, and concentrated under reduced pressure. The residue waspurified by column chromatography (5-10% gradient with ethyl acetate inhexane) to afford Intermediate-AA211-2. (7.4 g, 100%) MS (ES): m/z236[M+1]⁺

Step-2 Synthesis of methyl6-bromo-3-(2,2-difluoroethoxy)picolinate(Intermediate AA211-3)

To a solution of Intermediate AA198-4 (1.5 g, 46.55 mmol) in DMF (15 mL)were added potassium carbonate (2.6 g, 39.65 mmol, 3 eq) and dropwiseIntermediate-AA211-2 (1.98 g, 40.55 mmol, 0.3 eq). After stirring at100° C. and for 2 h, the reaction mixture was quenched with water (300mL) and extracted by EtOAc (2×100). The combined organic layer waswashed with brine (100 mL), passed through a Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by columnchromatography (5-10% gradient with ethyl acetate in hexane) to affordIntermediate AA211-3 (1.2 g, 98%), MS (ES): m/z 295[M+1]⁺.

Step-3 Synthesis of 6-bromo-3-(2,2-difluoroethoxy)pyridin-2-yl)methanol(Intermediate AA211-4)

To a solution of Intermediate AA211-3 (1 g, 33.89 mmol) in ethanol (20mL) was treated portion wise with sodium borohydride (0.380 g, 16.9mmol, 3.0 eq). After stirring at 80° C. for 1 h, the reaction wasquenched with water (200 mL) and extracted into ethyl acetate (3×80 mL).The combined organic extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography (20-30% gradient with ethyl acetate inhexane) to afford Intermediate AA211-4 (0.700 g, 100%). MS (ES): m/z=268[M+H]⁺.

Step-4 Synthesis of 1-(6-bromo-3-(2,2-difluoroethoxy)pyridin-2-yl)-N, Ndimethyl methanamine (Intermediate AA211)

To a solution of Intermediate AA211-4 (0.700 g, 26.11 mmol) in DCM (15mL) with diisopropylethylamine (1.0 mL, 35.73 mmol, 3.0 eq) at 0° C. wasadded mesyl chloride (0.446 g, 39.17 mmol, 1.5 eq). After stirring at 0°C. to RT for 30 mins, the reaction mixture was quenched with water (300mL) and extracted by DCM (2×100 mL). The combined organic layer waswashed with brine (100 mL), passed through a Na₂SO₄, and concentratedunder reduced to afford mesylate intermediate. (0.6 g, quantitative %),MS (ES): m/z 346 [M+1]⁺

To a solution of mesylate intermediate (0.600 g, 73.4 mmol) inacetonitrile (14 mL) was added dropwise diisopropylethylamine (0.7 mL,69.3 mmol, 3.5 eq). After stirring at 100° C. for 2 h, dimethylamine(0.280 g, 34.68 mmol, 2 eq) was added. After stirring at 100° C. for 2h, the reaction mixture was quenched with water (300 mL) and extractedby 10% methanol in DCM (2×100). The combined organic layer was washedwith brine (100 mL), passed through a Na₂SO₄, and concentrated underreduced pressure to afford Intermediate AA211 (035 g, 96%) which wasused as is, MS (ES): m/z 294 [M+1]⁺

Synthesis of6-((dimethylamino)methyl)-5-(3-(methoxymethyl)THF-3-yl)pyridin-2-amine(Intermediate-AA212)

Step-1 Synthesis oftert-butylbenzyl(6-((benzyloxy)methyl)-5-bromopyridin-2-yl)carbamate(Intermediate AA212-2)

To a solution of Intermediate AA188-1 (10 g, 33.00 mmol) in DMF (100 mL)at 0° C. was treated portion wise with sodium hydride (1.98 g, 25.08mmol, 2.5 eq). After stirring for 20 min at 0° C., mesyl chloride (2.75mLg, 35.64 mmol, 1.5 eq) was added dropwise. After stirring at 0° C. toRT for 10 min, benzyl bromide (16.9 g, 99.00 mmol,3.0 eq) was added.After stirring at rt for 3 h, the reaction mixture was quenched withsodium bicarbonate solution and extracted by EtOAc. The combined organiclayer was washed with brine (100 mL), passed through a Na₂SO₄, andconcentrated under reduced pressure. The residue was purified by columnchromatography (I-2% gradient of ethyl acetate in hexane) to affordIntermediate AA212-2 (9.3 g, 88%), MS (ES): m/z 483.41 [M+1]⁺

Step-2 Synthesis of tert-butylbenzyl(6-((benzyloxy)methyl)-5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)carbamate(Intermediate AA212-3)

To a solution of Intermediate AA212-2 (5 g, 68.60 mmol,1.0 eq) indioxane (100 mL) and water (50 mL) were added2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(4.7 g,27.54 mmol,1.1 eq) and add K₃PO₄ (13.15 g,58.90 mmol,3.0 eq).After degassing with argon for 10 mins,bis(triphenylphosphine)palladium(II) dichloride (1.45 g, 20.58 mmol,0.1eq) was added. After stirring at 80° C. for 1 h, the reaction mixturewas quenched with water and extracted by EtOAc. The combined organiclayer was washed with brine (100 mL), passed through a Na₂SO₄, andconcentrated under reduced pressure. The residue was purified by columnchromatography (12% gradient of ethyl acetate in hexane) to affordIntermediate AA212-3 (9.0 g, 99.38%), MS (ES): m/z 486 [M+1]⁺

Step-3 Synthesis of tert-butylbenzyl(6-((benzyloxy)methyl)-5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)carbamate(Intermediate AA212-4)

To a solution of Intermediate AA212-3 (10 g, 57.61 mmol) in DCM (125 mL)was treated portion wise with meta chloro per benzoic acid (8.89 g,40.20 mmol, 2.5 eq). After stirring at RT for 48 h, the reaction mixturewas cooled to RT, diluted with NaHCO₃ solution, and extracted into DCM(3×40 mL). The combined organic extracts were washed with brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography (10% gradient of EtOAc inHexane) to afford Intermediate AA212-4 (5 g, 89.73%), MS (ES): m/z 502[M+1]⁺

Step-4 Synthesis of tert-butylbenzyl(6-((benzyloxy)methyl)-5-(3-formylTHF-3-yl)pyridin-2-yl) carbamate (Intermediate AA212-5)

To a solution of Intermediate AA212-4 (10 g, 20.33 mmol) in dioxane (25mL) was treated portion wise with scandium(III) triflate (0.980 g, 19.92mmol, 0.1 eq). After stirring at 80° C. for 10 mins, the reactionmixture was cooled to RT, diluted with NaHCO₃ solution, and extractedinto ethyl acetate. The combined organic extracts were washed withbrine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography (12%gradient of EtOAc in hexane) to afford Intermediate AA212-5 (4.6 g,80%), MS (ES): m/z 502 [M+1]⁺

Step-5 Synthesis of tert-butyl benzyl(6-((benzyloxy)methyl)-5-(3-(hydroxymethyl)THF-3-yl)pyridin-2-yl)carbamate (Intermediate AA212-6)

To a solution of Intermediate AA212-5 (6 g, 19.52 mmol) in ethanol (25mL) at 0° C. was treated portion wise with sodium borohydride (1.36 g,58.56 mmol, 3.0 eq). After stirring for 10 mins, the reaction wasconcentrated under reduced pressure, quenched slowly with water (500mL), and extracted by DCM. The combined organic layer was washed withbrine dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography (18% gradient of ethylacetate in hexane) to afford Intermediate AA212-6 (3 g, 95%), MS (ES):m/z 504 [M+1]⁺

Step-6 Synthesis of tert-butylbenzyl(6-((benzyloxy)methyl)-5-(3-(methoxymethyl)THF-3-yl)pyridin-2-yl)carbamate (Intermediate AA212-7)

To a solution of Intermediate AA212-6 (1 g, 19.81 mmol) in THF (10 mL)and methanol (0.4 mL) at 0° C. was added sodium hydride (0.143 g,59.94mmol,3.0 eq). After stirring for 15 min, methyl iodide (0.42 g, 2.97mmol, 1.5 eq) was added. After stirring for 6 h, the reaction mixturewas quenched with water (300 mL) and extracted by ethyl acetate (2×100mL). The combined organic layer was washed with brine (100 mL), passedthrough a Na₂SO₄, and concentrated under reduced pressure. The residuewas purified by column chromatography (10% gradient of EtOAc in hexane)to afford Intermediate AA212-7 (0.900 g, 90%), MS (ES): m/z 515.65[M+1]⁺

Step-7 Synthesis of 6-(benzylamino)-3-(3-(methoxymethyl)THF-3-yl)pyridine-2-yl) methanol (Intermediate AA212-8)

To a solution of Intermediate AA212-7 (0.500 g, 9.64 mmol) in DCM (5 mL)at 0° C. was added dropwise triflic acid (0.3 mL). After stirring for 1h, the reaction mixture was quenched with sodium bicarbonate solution(300 mL) and extracted by DCM (2×100 mL). The combined organic layer waswashed with brine (100 mL), passed through a Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by columnchromatography (3% methanol gradient in DCM) to afford IntermediateAA212-8 (0.450 g, 81.92%), MS (ES): m/z 328.41 [M+1]⁺

Step-8 & 9 Synthesis ofN-benzyl-6-((dimethylamino)methyl)-5-(3-(methoxymethyl)THF-3-yl)pyridin-2-amine (Intermediate AA212-9)

To a solution of Intermediate AA211-8 (0.450 g, 37.02 mmol) in DCM (5mL) with diisopropylethylamine (0.240 g, 20.55 mmol, 1.5 eq) at 0° C.was added mesyl chloride (0.530 g, 11.06 mmol, 3.0 eq). After stirringat 0° C. to RT for 15 mins, the reaction mixture was quenched with water(300 mL) and extracted by DCM (2×100). The combined organic layer waswashed with brine (100 mL), passed through a Na₂SO₄, and concentratedunder reduced pressure to afford mesylated intermediate. (0.700 g, 74%),MS (ES): m/z 906.5 [M+1]⁺

To a solution of mesylated intermediate (0.7 g, 17.22 mmol) inacetonitrile (14 mL) was added dropwise diisopropylethylamine (1.33 g,33.22 mmol, 6.0 eq) and dimethylamine.hydrochloride (0.420 g, 51.66mmol, 3.0 eq). After stirring at 70° C. for 2 h, the reaction mixturewas cooled to RT, quenched with water (300 mL) and extracted by ethylacetate. The combined organic layer was washed with brine (100 mL),passed through a Na₂SO₄, and concentrated under reduced pressure. Theresidue was purified by column chromatography (5% methanol gradient inDCM) to afford Intermediate AA212-9 (0.450 g, 81.92%), MS (ES): m/z365.47 [M+1]⁺

Step-10 Synthesis of 6-((dimethylamino)methyl)-5-(3-(methoxymethyl)THF-3-yl)pyridin-2-amine (Intermediate AA212)

To a solution of Intermediate AA212-9 (0.400 g, 9.64 mmol) in DCM (1 mL)was added dropwise triflic acid (0.1 mL) at 0° C. After stirring for 20min, the reaction mixture was quenched with sodium bicarbonate solution(300 mL) and extracted by DCM (2×100 mL). The combined organic layer waswashed with brine (100 mL), passed through a Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by columnchromatography (3-4% methanol gradient in DCM) to afford IntermediateAA212 (0.190 g, 92%), MS (ES): m/z 265.36 [M+1]⁺

Synthesis of6-((dimethylamino)methyl)-5-(3-methylTHF-3-yl)pyridin-2-amine(Intermediate-AA213)

Step-1 & 2 synthesis of tert-butylbenzyl(6-((benzyloxy)methyl)-5-(3-methyl THF-3-yl)pyridin-2-yl)carbamate(Intermediate AA213-1)

To a solution of Intermediate AA212-6 (1.2 g, 20.68 mmol) in DCM (10 mL)at 0° C. with diisopropylethylamine (0.767 g, 59.52 mmol, 1.5 eq) wasadded mesyl chloride (0.339 g, 29.76 mmol, 3 eq). After stirring from 0°C. to RT for 15 min, the reaction mixture was quenched with water (300mL) and extracted by DCM (2×100). The combined organic layer was washedwith brine (100 mL), passed through Na₂SO₄, and concentrated underreduced pressure to afford mesylated intermediate. (1.2 g, 80%), MS(ES): m/z 582 [M+1]⁺ which was directly used for next step.

To a solution of mesylate intermediate (1.2 g, 20.68 mmol) in DMF (14mL) was added portion wise sodium iodide (1.53 g, 30.99 mmol, 5.0 eq)and portion wise zinc dust (2.0 g, 30.92 mmol, 15 eq). After stirring at130° C. for overnight, the reaction mixture was cooled to RT, quenchedwith water (300 mL) and extracted by ethyl acetate. The combined organiclayer was washed with brine (100 mL), passed through a Na₂SO₄, andconcentrated under reduced pressure. The residue was purified by columnchromatography (6.4% gradient of ethyl acetate in hexane) to affordIntermediate AA213-1 (0.300 g, 81%), MS (ES): m/z 488 [M+1]⁺

Step-3 Synthesis of6-(benzylamino)-3-(3-methylTHF-3-yl)pyridin-2-yl)methanol (IntermediateAA213-2)

To a solution of Intermediate AA213-1 (0.500 g, 9.64 mmol) in DCM (5 mL)at 0° C. was added dropwise triflic acid (0.3 mL). After stirring for 1h, the reaction mixture was quenched with sodium bicarbonate solution(300 mL) and extracted by DCM (2×100). The combined organic layer waswashed with brine (100 mL), passed through a Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by columnchromatography (3% methanol gradient in DCM) to afford IntermediateAA213-2 (0.270 g, 81.92%), MS (ES): m/z 298 [M+1]⁺

Step-4 & 5 Synthesis of N-benzyl-6-((dimethylamino)methyl)-5-(3-methyltetrahydrofuran-3-yl)pyridin-2-amine (Intermediate AA213-3)

To a solution of Intermediate AA213-2 (0.270 g, 37.02 mmol) in DCM (5mL) at 0° C. with Diisopropylethylamine (0.350 g, 20.55 mmol, 1.5 eq)was added mesyl chloride (0.154 g, 11.06 mmol, 3.0 eq). After stirringat 0° C. to RT for 15 mins, the reaction mixture was quenched with water(300 mL) and extracted by DCM (2×100). The combined organic layer waswashed with brine (100 mL), passed through a Na₂SO₄, and concentratedunder reduced pressure to afford mesylate intermediate (0.334 g, 72%),MS (ES): m/z 377 [M+1]⁺

To a solution of mesylate intermediate (0.334 g, 17.22 mmol) inacetonitrile (14 mL) was added dropwise diisopropylethylamine (0.685 g,33.22 mmol, 6.0 eq) and dropwise dimethylamine.hydrochloride (0.216 g,51.66 mmol, 3.0 eq). After stirring at 70° C. for 2 h, the reactionmixture was cooled to RT, quenched with water (300 mL) and extracted byethyl acetate. The combined organic layer was washed with brine (100mL), passed through a Na₂SO₄, and concentrated under reduced pressure.The residue was purified by column chromatography (5% methanol gradientin DCM) to afford Intermediate AA213-3 (0.260 g, 81%), MS (ES): m/z 325[M+1]⁺

Step-6 Synthesis of6-((dimethylamino)methyl)-5-(3-methylTHF-3-yl)pyridin-2-amine(Intermediate AA213)

To a solution of Intermediate AA213-3 (0.400 g, 9.64 mmol) in DCM (1 mL)at 0° C. was added dropwise triflic acid (2 mL). After stirring for 20mins, the reaction mixture was quenched with sodium bicarbonate solution(300 mL) and extracted with DCM (2×100 mL). The combined organic layerwas washed with brine (100 mL), dried with Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by columnchromatography (3-4% methanol gradient in DCM) to afford IntermediateAA213 (0.190 g, 95%), MS (ES): m/z 235 [M+1]⁺

The following intermediates in Table 2 were available commercially orprepared by known literature routes.

TABLE 2 Intermediates prepared by known literature routes orcommercially available. # Structure AA4 

AA5 

AA8 

AA11

AA12

AA16

AA17

AA24

AA26

AA27

AA28

AA29

AA31

AA33

AA35

AA36

AA38

AA40

AA41

AA42

AA44

AA45

AA46

AA47

AA53

AA57

AA60

AA61

AA62

AA68

AA71

AA75

AA76

AA79

AA82

Synthesis of tert-butyl(R)-(1-(6-aminopyridin-3-yl)piperidin-3-yl)(methyl)carbamate(Intermediate AB1) (Method A1)

Step 1: tert-Butyl(R)-methyl(1-(6-nitropyridin-3-yl)piperidin-3-yl)carbamate (IntermediateAB1-3)

A mixture of R)-tert-butyl-methyl(piperidin-3-yl)carbamate (IntermediateAB1-1) (1.00 g, 4.67 mmol) mmol), 5-fluoro-2-nitro-pyridine(Intermediate AB1-2) (660 mg, 4.67 mmol) and N,N-diisopropylethylamine(8.1 mL, 46.66 mmol) in DMSO (12 mL) was vigorously stirred and heatedat 120° C. for 1.5 h. The cooled mixture was diluted with water (50 mL)and extracted with EtOAc. The organic phase was dried by phase separatorand concentrated in vacuo. The residue was purified by columnchromatography (0-100% gradient elution EtOAc in cyclohexane) to affordthe title compound Intermediate AB1-3 (1.35 g, 86%) as a yellow oil.

¹H NMR (400 MHz, DMSO): δ 8.27 (d, J=3.0 Hz, 1H), 8.16 (d, J=9.3 Hz,1H), 7.50 (dd, J=3.1, 9.3 Hz, 1H), 4.11 (d, J=14.0 Hz, 1H), 3.97-3.74(m, 2H), 3.16 (dd, J=12.1, 12.1 Hz, 1H), 3.01-2.92 (m, 1H), 2.79 (s,3H), 1.88-1.77 (m, 3H), 1.62-1.55 (m, 1H), 1.43 (s, 9H).

Step 2: tert-Butyl(R)-(1-(6-aminopyridin-3-yl)piperidin-3-yl)(methyl)carbamate (AB1)

A solution of tert-butyl(R)-methyl(1-(6-nitropyridin-3-yl)piperidin-3-yl)carbamate (IntermediateAB1-3) (1.35 g, 4.01 mmol) in methanol (40 mL) was treated with 10%palladium on activated carbon (140 mg, 0.13 mmol). After stirring undera hydrogen atmosphere for 18 h, the mixture was filtered through Celite®washing with methanol and concentrated in vacuo azeotroping withDCM/Et₂O (1:1) to afford the title compound (Intermediate AB1) (1.29 g,quant.) as an orange glass solid.

¹H NMR (400 MHz, DMSO): δ 7.63 (d, J=2.6 Hz, 1H), 7.17 (dd, J=3.0, 8.8Hz, 1H), 6.40 (d, J=8.8 Hz, 1H), 5.41 (s, 2H), 3.97-3.97 (m, 1H), 3.28(d, J=12.0 Hz, 1H), 3.17 (s, 1H), 2.75 (s, 3H), 2.71-2.57 (m, 1H),2.49-2.41 (m, 1H), 1.79-1.54 (m, 4H), 1.42 (s, 9H).

Synthesis of tert-butylmethyl(4-methyl-1-(6-nitropyridin-3-yl)piperidin-4-yl)carbamate(Intermediate AB2)—Method B1

Step 1: tert-butylmethyl(4-methyl-1-(6-nitropyridin-3-yl)piperidin-4-yl)carbamate(Intermediate AB2-3)

Reaction performed analogous to the preparation of Intermediate AB1-3replacing N,N-diisopropylethylamine with 2.2 equivalents potassiumcarbonate. Intermediate AB2-3: ¹H NMR (400 MHz, CDCl3): δ 8.16 (d, J=9.0Hz, 1H), 8.13 (d, J=3.0 Hz, 1H), 7.18 (dd, J=3.1, 9.2 Hz, 1H), 3.62-3.54(m, 2H), 3.30-3.22 (m, 2H), 2.88 (s, 3H), 2.64-2.57 (m, 2H), 1.86-1.78(m, 2H), 1.55 (s, 3H), 1.47 (s, 9H).

Step 2: tert-butylmethyl(4-methyl-1-(6-nitropyridin-3-yl)piperidin-4-yl)carbamate (AB2)

Step 2 was carried out following the representative procedure describedin Intermediate AB1—Method A1, Step 2. Intermediate AB2: ¹H NMR (400MHz, CDCl3): δ 7.78 (d, J=2.6 Hz, 1H), 7.18 (dd, J=2.9, 8.8 Hz, 1H),6.48 (d, J=8.8 Hz, 1H), 4.17-4.11 (m, 2H), 3.11-3.04 (m, 2H), 2.98-2.90(m, 2H), 2.86 (s, 3H), 2.49-2.41 (m, 2H), 1.93-1.85 (m, 2H), 1.30 (s,3H).

Synthesis of S)-1-(1-(6-aminopyridin-3-yl)piperidin-4-yl)ethan-1-ol(Intermediate AB3) Method C1

Step 1: (S)-1-(1-(6-nitropyridin-3-yl)piperidin-4-yl)ethan-1-ol(Intermediate AB3-3)

A mixture of S)-1-(piperidin-4-yl)ethan-1-ol hydrochloride (IntermediateAB3-1) (0.82 g, 4.9 mmol) mmol), 5-bromo-2-nitro-pyridine (IntermediateAB3-2) (1.0 g, 4.9 mmol), tetrabutylammonium iodide (0.36 g, 9.8 mmol)and potassium carbonate (2.0 g, 14.7 mmol) in DMSO (10 mL) was heated at120° C. for 1 h. The cooled mixture was diluted with water (50 mL) andextracted with EtOAc (2×50 mL). The organic phase was dried over MgSO4,filtered, and concentrated in vacuo. The residue was purified by columnchromatography (0-100% gradient elution EtOAc in cyclohexane) to affordthe title compound (Intermediate AB3-3) (0.91 g, 73%) as an orangesolid.

¹H NMR (400 MHz, DMSO): δ 8.23 (d, J=3.3 Hz, 1H), 8.12 (d, J=9.1 Hz,1H), 7.44 (dd, J=3.0, 9.3 Hz, 1H), 4.43 (d, J=5.1 Hz, 1H), 4.16-4.11 (m,2H), 3.39 (dd, J=7.1, 11.4 Hz, 1H), 3.00-2.89 (m, 2H), 1.87 (d, J=13.1Hz, 1H), 1.65 (d, J=12.6 Hz, 1H), 1.53-1.42 (m, 1H), 1.35-1.17 (m, 2H),1.04 (d, J=6.3 Hz, 3H).

Step 2: (S)-1-(1-(6-aminopyridin-3-yl)piperidin-4-yl)ethan-1-ol (AB3)

Step 2 was carried out following the representative procedure describedin Intermediate AB1, Step 2. AB3: ¹H NMR (400 MHz, DMSO): δ 7.59 (d,J=2.8 Hz, 1H), 7.14 (dd, J=3.0, 8.8 Hz, 1H), 6.38 (d, J=8.8 Hz, 1H),5.33 (s, 2H), 4.36 (d, J=4.5 Hz, 1H), 3.42-3.35 (m, 3H), 2.48-2.39 (m,2H), 1.86-1.80 (m, 1H), 1.64-1.57 (m, 1H), 1.39-1.18 (m, 3H), 1.04 (d,J=6.3 Hz, 3H).

Synthesis of 2-(6-aminopyridin-3-yl)-N-ethyl-2-methylpropanamide(Intermediate AB4)—Method D1

Step 1: Ethyl 2-methyl-2-(6-nitropyridin-3-yl)propanoate (IntermediateAB4-2)

A solution of ethyl-2-(6-nitropyridin-3-yl)acetate (Intermediate AB4-1)(980 mg, 4.6 mmol) in DMF (20 mL) at 0° C. was treated with sodiumhydride (60% dispersion in mineral oil, 196 mg, 4.8 mmol). The mixturewas stirred for 5 min, and then iodomethane (0.316 mL, 5.0 mmol) wasadded dropwise. After 2 h, an additional portion of sodium hydride (60%dispersion in mineral oil, 196 mg, 4.8 mmol) was added, followed byiodomethane (0.316 mL, 5.0 mmol) 5 min later. The mixture was stirred atRT for 18 h, quenched with water (30 mL) and extracted into EtOAc (2×30mL). The combined extracts were washed with brine (30 mL), dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bycolumn chromatography (0-50% gradient elution EtOAc in cyclohexane) toafford the title compound (Intermediate AB4-2) (758 mg, 68%) as a yellowoil.

¹H NMR (400 MHz, CDCl3): δ 8.63 (s, 1H), 8.22 (d, J=8.4 Hz, 1H), 7.99(d, J=8.2 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 1.67 (s, 6H), 1.20 (t, J=7.2Hz, 3H)

Step 2: 2-Methyl-2-(6-nitropyridin-3-yl)propanoic acid (IntermediateAB4-3)

A solution of ethyl 2-methyl-2-(6-nitropyridin-3-yl)propanoate(Intermediate AB4-2) (750 mg, 3.1 mmol) in methanol:water (14 mL, 1:1)was treated with lithium hydroxide monohydrate (198 mg, 4.7 mmol). Afterstirring at RT overnight, the pH was adjusted to −5 using 1M aqueous HClsolution and extracted with 9:1 DCM-MeOH (3×25 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo toafford the title compound as a crude, off white solid (IntermediateAB4-2) (423 mg, 63%).

¹H NMR (400 MHz, DMSO): δ 12.87 (s, 1H), 8.67 (d, J=1.8 Hz, 1H), 8.28(d, J=8.6 Hz, 1H), 8.19 (dd, J=2.4, 8.5 Hz, 1H), 1.59 (s, 6H).

Step 3: N-Ethyl-2-methyl-2-(6-nitropyridin-3-yl)propenamide(Intermediate AB4-4)

To a suspension of 2-methyl-2-(6-nitropyridin-3-yl)propanoic acid(Intermediate AB4-3) (430 mg, 2.0 mmol) in THF (5 mL) were added1-hydroxybenzotriazole (359 mg, 2.6 mmol) andN-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (510 mg,2.6 mmol). After stirring for 10 min at RT, DIPEA (1.069 mL, 6.1 mmol)and ethylamine (2M solution in THF, 2.04 mL, 4.0 mmol) were added. Afterstirring overnight at RT, the reaction was diluted with EtOAc (20 mL).The organic phase was washed with water (15 mL) and brine (15 mL), dried(MgSO4), filtered and concentrated in vacuo. The residue was purified bycolumn chromatography (0-100% gradient elution EtOAc in cyclohexane) toafford the title compound (Intermediate AB4-4) (375 mg, 77%) as a paleyellow oil.

¹H NMR (400 MHz, DMSO): δ 8.58 (d, J=2.0 Hz, 1H), 8.27 (d, J=7.8 Hz,1H), 8.10 (dd, J=2.4, 8.5 Hz, 1H), 7.60 (dd, J=6.2, 6.2 Hz, 1H),3.11-3.03 (m, 2H), 1.53 (s, 6H), 0.97 (dd, J=7.2, 7.2 Hz, 3H).

Step 4: 2-(6-Aminopyridin-3-yl)-N-ethyl-2-methylpropanamide (AB4)

Step 4 was carried out following the representative procedure describedin Intermediate AB1, Step 2.

¹H NMR (400 MHz, DMSO): δ 7.83 (d, J=2.0 Hz, 1H), 7.26 (dd, J=2.5, 8.6Hz, 2H), 6.38 (d, J=8.1 Hz, 1H), 5.74 (s, 2H), 3.05-3.01 (m, 2H), 1.36(s, 6H), 0.93 (t, J=7.0 Hz, 3H).

Synthesis of tert-butyl(1-(6-aminopyridin-2-yl)piperidin-4-yl)(methyl)carbamate (IntermediateAB5) Method E1

Step 1: tert-Butyl(1-(6-aminopyridin-2-yl)piperidin-4-yl)(methyl)carbamate (IntermediateAB5)

A mixture of tert-butyl methyl(piperidin-4-yl)carbamate (IntermediateAB31-1) (3.33 g, 15.56 mmol) and 6-chloro-2-amino-pyridine (IntermediateAB5-2) (1.00 g, 7.78 mmol) were heated neat at 140° C. for 18 h. Thecooled mixture was diluted with EtOAc and concentrated in vacuo. Theresidue was purified by column chromatography (0-10% gradient elutionMeOH in DCM) to afford the title compound (Intermediate AB5) (612 mg,26%) as a red oil.

¹H NMR (400 MHz, CDCl₃): δ, 7.25-7.23 (m, 1H), 6.02 (d, J=8.1 Hz, 1H),5.85 (d, J=7.6 Hz, 1H), 5.30 (s, 2H), 4.35 (d, J=12.6 Hz, 2H), 4.18 (d,J=16.2 Hz, 2H), 2.81-2.76 (m, 1H), 2.71 (s, 3H), 1.69 (s, 9H), 1.57 (s,4H).

Synthesis of tert-butyl(S)-(1-(6-aminopyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate(Intermediate AB6)—Method F1

Step 1: tert-Butyl(S)-methyl(1-(6-nitropyridin-2-yl)pyrrolidin-3-yl)carbamate(Intermediate AB6-3)

A mixture of 2-bromo-6-nitro-pyridine (Intermediate AB6-2) (1.00 g, 4.93mmol), tert-butyl-(S)-methyl(pyrrolidin-3-yl) carbamate (IntermediateAB6-1) (1.09 g, 5.42 mmol), XantPhos (0.29 g, 0.493 mmol), Pd₂(dba)₃(0.36 g, 0.394 mmol) and cesium carbonate (3.21 g, 9.85 mmol) in toluene(40 mL) was degassed with nitrogen and heated at 95° C. for 4 h. Thecooled reaction mixture was concentrated in vacuo and the residuepartitioned between EtOAc and water. The aqueous layer was furtherextracted with EtOAc (2×). The combined extracts were dried over MgSO4and concentrated in vacuo. The residue was purified by columnchromatography (0-75% gradient elution EtOAc in cyclohexane) to affordthe title compound (Intermediate AB6-3) (523 mg, 33%) as a yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 7.67 (t, J=7.9 Hz, 1H), 7.43 (d, J=7.0 Hz,1H), 6.64 (d, J=8.8 Hz, 1H), 4.92 (s, 1H), 3.75 (t, J=10.2 Hz, 2H), 3.50(dd, J=8.2, 19.3 Hz, 1H), 3.41 (dd, J=8.5, 10.8 Hz, 1H), 2.83 (s, 3H),2.27-2.14 (m, 2H), 1.48 (s, 9H).

Step 2: tert-Butyl(S)-(1-(6-aminopyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate(Intermediate AB6)

Step 2 was carried out following the representative procedure describedin Intermediate AB1—Method A1, Step 2. AB6: ¹H NMR (400 MHz, CDCl₃): δ7.24 (t, J=8.0 Hz, 1H), 5.81 (d, J=7.7 Hz, 1H), 5.74 (d, J=8.0 Hz, 1H),4.85 (s, 1H), 4.19 (s, 2H), 3.64-3.55 (m, 2H), 3.37-3.34 (m, 1H),3.33-3.27 (m, 1H), 2.80 (s, 3H), 2.19-2.09 (m, 1H), 2.07-1.98 (m, 1H),1.48 (s, 9H).

Synthesis of N²-(2-(dimethylamino)ethyl)-N²-methylpyridine-2,6-diamine(Intermediate AB7)

Step 1: N²-(2-(dimethylamino)ethyl)-N²-methylpyridine-2,6-diamine (AB7)

A mixture of 6-bromo-2-amino-pyridine (Intermediate AB7-2) (500 mg, 2.89mmol), N, N, N′-trimethylethylenediamine (Intermediate AB7-1) (591 mg,5.78 mmol) and cesium carbonate (1.41 g, 4.33 mmol) in NMP (10 mL) washeated at 200° C. for 20 min using microwave irradiation (BiotageInitiator®). The mixture was poured onto water and extracted into EtOAc(3×). The combined organic layers were dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by column chromatography(0-20% gradient elution with MeOH in DCM followed by 1:1 7N methanolicammonia in DCM) to afford the title compound (Intermediate AB7) (581 mg,quant.) as a red/orange residue.

¹H NMR (400 MHz, CDCl₃) 7.22 (t, J=7.8 Hz, 1H), 5.85 (d, J=8.8 Hz, 1H),5.77 (d, J=7.9 Hz, 1H), 4.20 (s, 2H), 3.61 (t, J=7.6 Hz, 2H), 2.98 (s,3H), 2.46 (t, J=7.5 Hz, 2H), 2.29 (s, 6H)

Synthesis of tert-butyl(1-(6-aminopyridin-3-yl)-3,3-difluoropiperidin-4-yl)(methyl)carbamate(Intermediate AB48)—Method H1

Step 1: tert-butyl(3,3-difluoro-1-(6-nitropyridin-3-yl)piperidin-4-yl)carbamate(Intermediate AB48-2)

Step 1 was carried out following the representative procedure describedin Intermediate AB1—Method A1, Step 1 using4-(Boc-amino)-3,3-difluoropiperidine (Intermediate AB48-1) to afford thetitle compound (Intermediate AB48-2) as a yellow solid. ¹H NMR (400 MHz,CDCl₃): δ 8.20-8.16 (m, 2H), 7.28 (dd, J=2.1, 8.3 Hz, 1H), 4.80 (s, 1H),4.23-4.16 (m, 1H), 4.02 (dd, J=2.3, 13.7 Hz, 1H), 3.39-3.27 (m, 1H),3.24-3.16 (m, 1H), 2.22-2.14 (m, 1H), 1.79 (ddt, J=4.1, 12.7, 12.5 Hz,1H).

Step 2: tert-butyl(3,3-difluoro-1-(6-nitropyridin-3-yl)piperidin-4-yl)(methyl)carbamate(Intermediate AB48-3)

A solution of tert-butyl(3,3-difluoro-1-(6-nitropyridin-3-yl)piperidin-4-yl)carbamate(Intermediate AB48-2) (370 mg, 1.03 mmol) and iodomethane (161 mg, 1.14mmol) in DMF (3 mL) was treated with sodium hydride (60% dispersion inmineral oil, 45 mg, 1.14 mmol). After stirring and stirred at RT for 1.5h, the reaction was quenched with a saturated NaHCO₃ solution andextracted into EtOAc (2×). The combined extracts were dried over MgSO4and concentrated in vacuo. The residue was purified by columnchromatography (10-70% gradient elution EtOAc in cyclohexane) to affordthe title compound (Intermediate AB48-3) (274 mg, 71%) as a yellowsolid.

¹H NMR (400 MHz, CDCl₃): δ 8.20-8.17 (m, 2H), 7.31-7.27 (m, 1H),4.78-4.77 (m, 1H), 3.36-3.19 (m, 2H), 2.88 (s, 3H), 2.23-2.16 (m, 1H),1.94-1.93 (m, 1H), 1.59 (s, 1H).

Step 3: tert-butyl(1-(6-aminopyridin-3-yl)-3,3-difluoropiperidin-4-yl)(methyl)carbamate(AB48)

Step 3 was carried out following the representative procedure describedin Intermediate AB1—Method A, Step 2 to afford the title compound (AB48)(258 mg) as a yellow residue which was used crude in subsequentreactions.

Synthesis of 6-((dimethylamino)methyl)-5-(THF-3-yl)pyridin-2-amine(Intermediate AB50)—Method I1

Step 1: Methyl 6-(bis(tert-butoxycarbonyl)amino)-3-bromopicolinate(Intermediate AB50-2)

A solution of methyl 6-amino-3-bromopicolinate (Intermediate AB50-1)(2.00 g, 8.7 mmol) and DMAP (0.21 g, 1.7 mmol) in THF (50 mL) was cooledto 0° C., treated portion wise with di-tert-butyl dicarbonate (2.27 g,10.4 mmol), and then heated at 60° C. for 16 h. The reaction was cooledto RT, then treated portion wise with further di-tert-butyl dicarbonate(2.27 g, 10.4 mmol) and heated at 60° C. for 5 h. After cooling to RT,the solvent was removed in vacuo and the residue partitioned betweenEtOAc (3×30 mL) and saturated aqueous sodium bicarbonate (20 mL). Thecombined organic phase was washed with brine (20 mL), passed through ahydrophobic filter and concentrated in vacuo. The residue was purifiedby column chromatography (0-30% gradient elution EtOAc in cyclohexane)to afford the title compound (Intermediate AB50-2) (3.37 g, 7.8 mmol,90%) as a colourless oil, which solidified on standing to a white solid.¹H NMR (400 MHz, CDCl₃): δ 7.98 (d, J=8.5 Hz, 1H), 7.33 (d, J=8.3 Hz,1H), 3.96 (s, 3H), 1.46 (s, 18H).

Step 2: tert-Butyl(5-bromo-6-(hydroxymethyl)pyridin-2-yl)(tert-butoxycarbonyl)carbamate(Intermediate AB50-3) and tert-butyl(5-bromo-6-(hydroxymethyl)pyridin-2-yl)carbamate (Intermediate AB50-3′)

A solution of Intermediate AB50-2) (3.37 g, 7.8 mmol) in ethanol (40 mL)was treated portion wise with sodium borohydride (0.89 g, 23.4 mmol).After stirring at RT for 16 h, the reaction was quenched dropwise withwater (10 mL), and the ethanol removed in vacuo. The residue wasextracted into EtOAc (3×20 mL). The combined organic phases were washedwith brine (10 mL), passed through a hydrophobic filter, andconcentrated in vacuo. The residue was purified by column chromatography(0-50% gradient elution EtOAc in cyclohexane) affording a 1:1inseparable mixture of Intermediate AB50-3) and (Intermediate AB50-3′)(1.86 g) as an oily white solid.

¹H NMR (400 MHz, CDCl₃): δ 7.87 (d, J=8.3 Hz, 1H), 7.82-7.76 (m, 2H),7.23 (s, 1H), 7.19 (d, J=8.5 Hz, 1H), 4.72 (d, J=4.4 Hz, 2H), 4.66 (d,J=4.6 Hz, 2H), 3.88 (t, J=4.8 Hz, 1H), 3.86 (t, J=4.9 Hz, 1H), 1.53 (s,9H), 1.48 (s, 18H)—1:1 mixture of di-Boc and mono-Boc

Step 3: tert-Butyl(5-bromo-6-((dimethylamino)methyl)pyridin-2-yl)carbamate (IntermediateAB50-4)

To a solution of Intermediate AB50-3 and Intermediate AB50-3′ mixture(1.77 g, 4.9 mmol) in acetonitrile (35 mL) at 0° C. were added DIPEA(3.1 mL, 17.6 mmol) and methane sulfonyl chloride (0.68 mL, 8.8 mmol).After stirring for 20 min at 0° C., then warming to RT for 1.5 h, thereaction was quenched with water (40 mL) and extracted into DCM (3×40mL). The combined organic phases were washed with brine, passed througha hydrophobic filter, and concentrated in vacuo. The residue wasdissolved in acetonitrile (35 mL), treated with dimethylaminehydrochloride (4.29 g, 52.7 mmol) and potassium carbonate (7.28 g, 52.7mmol) and heated at reflux for 16 h. The reaction mixture was filteredand concentrated in vacuo. The residue was purified by columnchromatography (0-100% gradient elution EtOAc in cyclohexane followed by0-10% 7N methanolic ammonia in EtOAc) to afford the title compound(Intermediate AB50-4) (1.16 g, 71%) as a yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 7.76 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.6 Hz,1H), 7.37 (s, 1H), 3.60 (s, 2H), 2.33 (s, 6H), 1.51 (s, 9H).

Step 4: tert-Butyl(5-(2,5-dihydrofuran-3-yl)-6-((dimethylamino)methyl)pyridin-2-yl)carbamate(Intermediate AB50-5)

A mixture of Intermediate AB50-4 (1.16 g, 3.5 mmol),2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.76g, 3.9 mmol), XPhos-Pd-Gen4 (0.30 g, 0.35 mmol), XPhos (0.17 g, 0.35mmol) and potassium phosphate tribasic (1.49 g, 7.0 mmol) was suspendedin 1,4-dioxane (17 mL) and water (2 mL), degassed with nitrogen. Afterheating at 110° C. using microwave irradiation (Biotage Initiator®) for1 h, the cooled mixture was diluted with water (30 mL) and extractedinto EtOAc (3×50 mL). The combined extracts were washed with brine (40mL), passed through a hydrophobic filter and concentrated in vacuo. Theresidue was purified by column chromatography (0-20% gradient elution 7Nmethanolic ammonia in EtOAc) to afford the title compound (IntermediateAB50-5) (737 mg, 66%) as a yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 7.80 (d, J=8.3 Hz, 1H), 7.45 (d, J=8.5 Hz,1H), 7.36 (s, 1H), 6.10 (s, 1H), 4.88 (s, 4H), 3.47 (s, 2H), 2.26 (s,6H), 1.51 (s, 9H).

Step 5: 6-((Dimethylamino)methyl)-5-(THF-3-yl)pyridin-2-amine (AB50)

A solution of Intermediate AB50-5) (470 mg, 1.5 mmol) in methanol (5 mL)and ethanol (15 mL) was treated with 10% palladium on carbon (157 mg, 10mol %). After stirring under an atmosphere of hydrogen gas at RT for 36h, the reaction mixture was filtered through Celite® and concentrated invacuo. The crude product was dissolved in DCM (5 mL), treated dropwisewith trifluoroacetic acid (3.0 mL, 39.2 mmol) and stirred at RT for 3 h.The solvent was removed in vacuo and The residue purified by Isolute®SCX-2 cartridge eluting with 0-10% methanol/DCM followed by 10% 7Nmethanolic ammonia in DCM to afford the title compound (AB50) (276 mg,85%) as an off-white solid.

¹H NMR (400 MHz, CDCl₃): δ 7.40 (d, J=8.5 Hz, 1H), 6.43 (d, J=8.1 Hz,1H), 4.34 (s, 2H), 4.08-4.00 (m, 2H), 3.90 (td, J=7.6, 8.6 Hz, 1H),3.81-3.73 (m, 1H), 3.62 (dd, J=6.6, 8.3 Hz, 1H), 3.51 (d, J=12.4 Hz,1H), 3.42 (d, J=12.4 Hz, 1H), 2.36-2.26 (m, 1H), 2.25 (s, 6H), 1.91-1.81(m, 1H).

Synthesis of tert-butyl(S)-((4-(6-aminopyridin-3-yl)morpholin-2-yl)methyl)(cyclopropyl)carbamate(Intermediate AB53)—Method J1

Intermediate AB45-2 was prepared following analogous procedure toIntermediate AB1—Method A1, Step 1 using (S)-morpholin-2-ylmethanol.

Step 1: (S)-(4-(6-Nitropyridin-3-yl)morpholin-2-yl)methylmethanesulfonate (Intermediate AB53-1)

A solution of S)-(4-(6-nitropyridin-3-yl)morpholin-2-yl)methanol(Intermediate AB44-2) (600 mg, 2.51 mmol) and N,N-diisopropylethylamine(2.2 mL, 12.54 mmol) in acetonitrile (25 mL) at 0° C. was treateddropwise with methanesulfonyl chloride (0.58 mL, 7.52 mmol). After 1.5h, the reaction was quenched with water and extracted into EtOAc (3×).The combined extracts were dried over MgSO4 and concentrated in vacuo toafford the title compound (Intermediate AB53-1) (700 mg, 88%) as anorange solid which was used as is in subsequent reactions.

Step 2:(R)—N-((4-(6-Nitropyridin-3-yl)morpholin-2-yl)methyl)cyclopropanamine(Intermediate AB53-2)

A mixture of S)-(4-(6-nitropyridin-3-yl)morpholin-2-yl)methylmethanesulfonate (Intermediate AB53-1) (700 mg, 2.21 mmol),cyclopropylamine (0.76 mL, 11.03 mmol) and potassium carbonate (915 mg,6.62 mmol) in acetonitrile (10 mL). After stirring at 80° C. for 16 h,the cooled reaction mixture was filtered, concentrated in vacuo andpurified by column chromatography (0-20% methanol gradient in DCM) toafford the title compound (Intermediate AB53-2) (720 mg, quant.) as ayellow oil. ¹H NMR (400 MHz, DMSO): δ 8.32 (d, J=3.6 Hz, 1H), 8.23 (d,J=8.8 Hz, 1H), 7.54 (dd, J=3.4, 9.2 Hz, 1H), 4.05 (d, J=11.9 Hz, 2H),3.94 (d, J=12.1 Hz, 1H), 3.70-3.63 (m, 2H), 3.06 (ddd, J=12.2, 12.2, 4.2Hz, 1H), 2.82-2.76 (m, 3H), 2.17 (ddd, J=3.5, 6.5, 10.0 Hz, 1H), 0.42(ddd, J=6.4, 6.4, 4.4 Hz, 2H), 0.28 (ddd, J=3.6, 3.6, 6.2 Hz, 2H).

Step 3: tert-Butyl(S)-cyclopropyl((4-(6-nitropyridin-3-yl)morpholin-2-yl)methyl)carbamate(Intermediate AB53-3)

A solution ofR)—N-((4-(6-nitropyridin-3-yl)morpholin-2-yl)methyl)cyclopropanamine(Intermediate AB53-2) (800 mg, 2.87 mmol), di-tert-butyl dicarbonate(721 mg, 3.31 mmol), DMAP (35 mg, 0.287 mmol) and triethylamine (0.76mL, 8.62 mmol) in DCM (30 mL) was stirred at RT for 16 h. The mixturewas washed with a saturated NaHCO₃ solution, the organic phase driedover MgSO4 and concentrated in vacuo. The residue was purified byIsolute SCX-2 cartridge eluting with DCM to afford the title compound(Intermediate AB53-3) (907 mg, quant.) as a yellow oil.

¹H NMR (400 MHz, DMSO): δ 8.30 (d, J=2.9 Hz, 1H), 8.24 (d, J=9.3 Hz,1H), 7.55 (dd, J=3.2, 9.5 Hz, 1H), 4.06 (dd, J=12.1, 20.8 Hz, 2H),3.96-3.91 (m, 2H), 3.83 (d, J=8.7 Hz, 1H), 3.67 (t, J=11.1 Hz, 2H),3.15-3.05 (m, 1H), 2.82 (dd, J=11.7, 11.7 Hz, 1H), 2.66-2.61 (m, 1H),1.46 (s, 9H), 0.75 (d, J=5.4 Hz, 2H), 0.70-0.67 (m, 1H), 0.62-0.59 (m,1H).

Step 4: tert-Butyl(S)-((4-(6-aminopyridin-3-yl)morpholin-2-yl)methyl)(cyclopropyl)carbamate(AB53)

Step 4 was carried out following the representative procedure describedin Intermediate AB1—Method A1, Step 2.

¹H NMR (400 MHz, DMSO): δ 7.64 (d, J=3.1 Hz, 1H), 7.22 (dd, J=3.3, 8.9Hz, 1H), 6.47 (d, J=8.5 Hz, 1H), 5.49 (s, 2H), 3.97-3.91 (m, 3H),3.83-3.78 (m, 1H), 3.71-3.61 (m, 2H), 3.33-3.28 (m, 2H), 2.64 (ddd,J=11.4, 11.4, 3.7 Hz, 1H), 2.37 (t, J=9.3 Hz, 1H), 1.46 (s, 9H), 0.74(d, J=8.5 Hz, 2H), 0.67-0.63 (m, 1H), 0.60-0.57 (m, 1H).

Synthesis of1-(6-aminopyridin-3-yl)-3-((3-fluoroazetidin-1-yl)methyl)piperidin-3-ol(Intermediate AB59)—Method K1

Step 1: tert-butyl3-((3-fluoroazetidin-1-yl)methyl)-3-hydroxypiperidine-1-carboxylate(Intermediate AB59-2)

To a solution of tert-butyl 1-oxa-5-azaspiro[2.5]octane-5-carboxylate(1.0 g, 4.6 mmol) and 3-fluoroazetidine hydrochloride (1.05 g, 9.3 mmol)in ethanol (15 mL) and water (1.7 mL) was added triethylamine (2 mL,14.0 mmol). After heating at 100° C. using microwave irradiation(Biotage Initiator®) for 3 h, the mixture was concentrated in vacuo. Theresidue was purified by column chromatography (0-10% gradient elution 7Nmethanolic ammonia in EtOAc/cyclohexane) to afford the title compound(Intermediate AB59-2) (1.08 g, 80%) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 5.22-5.00 (m, 1H), 3.86-3.72 (m, 2H),3.42-3.39 (m, 1H), 3.33 (ddd, J=4.1, 6.7, 9.7 Hz, 2H), 3.27-3.22 (m,1H), 3.11 (s, 2H), 2.60 (d, J=12.9 Hz, 1H), 2.46 (d, J=13.3 Hz, 1H),1.77-1.71 (m, 2H), 1.62-1.54 (m, 2H).

Step 2: 3-((3-fluoroazetidin-1-yl)methyl)piperidin-3-ol (IntermediateAB59-3)

To a stirred solution of tert-butyl3-((3-fluoroazetidin-1-yl)methyl)-3-hydroxypiperidine-1-carboxylate(Intermediate AB59-2) (1.28 g, 4.4 mmol) in DCM (11 mL) at 0° C. wasadded trifluoroacetic acid (4 mL). After stirring for 4 h allowingwarming to RT, the mixture was concentrated in vacuo. The residue waspurified by Isolute® SCX-2 cartridge eluting with 20% 7N methanolicammonia in DCM to afford the title compound (Intermediate AB59-3) (790mg, 94%) as a yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 5.21-5.00 (m, 1H), 3.79-3.69 (m, 2H), 3.48(s, 1H), 3.38-3.25 (m, 2H), 2.97 (d, J=12.4 Hz, 1H), 2.77 (d, J=12.4 Hz,1H), 2.60-2.51 (m, 2H), 2.50 (d, J=2.9 Hz, 2H), 1.79 (ddd, J=7.9, 3.7,25.1 Hz, 1H), 1.63-1.55 (m, 1H), 1.54-1.46 (m, 1H), 1.39-1.30 (m, 1H).

Step 3:3-((3-fluoroazetidin-1-yl)methyl)-1-(6-nitropyridin-3-yl)piperidin-3-ol(Intermediate AB59-4)

Step 3 was carried out following the representative procedure describedin Intermediate AB2—Method B1, Step 1.

¹H NMR (400 MHz, CDCl₃): δ 8.14 (dd, J=3.0, 6.1 Hz, 2H), 7.20 (dd,J=3.2, 9.2 Hz, 1H), 5.25-5.05 (m, 1H), 3.85-3.74 (m, 2H), 3.69-3.61 (m,1H), 3.50-3.35 (m, 3H), 3.26-3.14 (m, 2H), 2.89 (s, 1H), 2.65 (d, J=13.1Hz, 1H), 2.55 (d, J=13.1 Hz, 1H), 2.03-1.92 (m, 1H), 1.73-1.66 (m, 2H).

Step 4: Synthesis of1-(6-aminopyridin-3-yl)-34(3-fluoroazetidin-1-yl)methyl)piperidin-3-ol(AB59)

Step 4 was carried out following the representative procedure describedin Intermediate AB1—Method A1, Step 2.

¹H NMR (400 MHz, CDCl₃): δ 8.16-8.12 (m, 2H), 7.25-7.20 (m, 1H),5.26-5.07 (m, 1H), 3.68-3.61 (m, 1H), 3.54 (d, J=13.1 Hz, 1H), 3.28-3.21(m, 2H), 3.11-2.94 (m, 4H), 2.74-2.69 (m, 2H), 2.59 (dd, J=1.5, 13.6 Hz,1H), 2.18-1.96 (m, 3H), 1.80-1.61 (m, 3H).

Synthesis of 3S)-1-(1-(6-aminopyridin-3-yl)ethyl)piperidin-3-ol(Intermediate AB71)—Method L1

1-(6-bromopyridin-3-yl)ethyl methanesulfonate (Intermediate AB71-1) wasprepared as described in US20200038378.

Step 1: (3S)-1-(1-(6-bromopyridin-3-yl)ethyl)piperidin-3-ol(Intermediate AB71-2)

Step 1 was performed according to the procedure described inIntermediate AB53—Method J1, Step 2 using (S)-piperidin-3-ol.

¹H NMR (400 MHz, DMSO): δ 8.31 (s, 1H), 7.68 (dd, J=2.5, 8.2 Hz, 1H),7.60 (dd, J=2.6, 8.0 Hz, 1H), 4.54 (dd, J=5.1, 9.5 Hz, 1H), 3.60 (ddd,J=6.7, 13.6, 18.7 Hz, 1H), 3.47-3.36 (m, 1H), 2.76 (ddd, J=11.9, 11.9,4.0 Hz, 1H), 2.69 (dd, J=3.7, 10.0 Hz, 1H), 2.56 (d, J=11.2 Hz, 1H),1.85-1.71 (m, 1H), 1.66-1.58 (m, 1H), 1.38 (td, J=3.1, 11.2 Hz, 1H),1.28 (d, J=6.9 Hz, 3H), 1.05-0.91 (m, 1H).

Step 2: tert-Butyl(5-(14(S)-3-hydroxypiperidin-1-yl)ethyl)pyridin-2-yl)carbamate(Intermediate AB71-3)

Step 2 was performed according to the procedure described inIntermediate AB6—Method F1, Step 1 using tert-butyl carbamate.

¹H NMR (400 MHz, DMSO): δ 9.68 (s, 1H), 8.12 (dd, J=2.4, 2.4 Hz, 1H),7.73 (d, J=8.9 Hz, 1H), 7.63 (td, J=2.1, 8.9 Hz, 1H), 4.56-4.49 (m, 1H),3.56-3.49 (m, 1H), 3.44-3.37 (m, 1H), 2.77-2.67 (m, 2H), 2.59 (d, J=10.5Hz, 1H), 1.79-1.73 (m, 2H), 1.63-1.56 (m, 2H), 1.46 (s, 9H), 1.28 (d,J=6.7 Hz, 6H).

Step 3: (3S)-1-(1-(6-aminopyridin-3-yl)ethyl)piperidin-3-ol (AB71)

Step 3 was performed according to the procedure described inIntermediate AB50—Method I1, Step 5 [TFA/DCM treatment only] to affordthe title compound (AB71) as a yellow residue which was used crude insubsequent reactions.

Synthesis of(R)-1-(6-bromo-3-((THF-3-yl)oxy)pyridin-2-yl)-N,N-dimethylmethanamine(Intermediate AB84)—Method M1

Step 1: Methyl 6-bromo-3-((tert-butyldimethylsilyl)oxy)picolinate(Intermediate AB84-2)

A mixture of methyl-6-bromo-3-hydroxypyridine-2-carboxylate(Intermediate AB84-1) (2.50 g, 10 77 mmol), TBDMSCl (2.44 g, 16.16 mmol)and imidazole (1.10 g, 16.16 mmol) in DCM (30 mL) was stirred at RT for18 h. The reaction was diluted with DCM and washed with water. Theorganic solution was washed with brine, dried over Na₂SO₄, andconcentrated in vacuo to leave the title compound (Intermediate AB84-2)(3.21 g, 9.27 mmol) as a pale yellow oil which was used crude insubsequent reactions.

Step 2: 6-Bromo-3-((tert-butyldimethylsilyl)oxy)picolinaldehyde(Intermediate AB84-3)

A solution of methyl 6-bromo-3-((tert-butyldimethylsilyl)oxy)picolinate(Intermediate AB84-2) (3.20 g, 9.24 mmol) in DCM (30 mL) at −78° C.under a nitrogen atmosphere was treated dropwise with DIBAL-H (1.5Msolution in toluene, 13.6 mL, 20.33 mmol). After stirring cold for 3 h,the reaction was quenched with Rochelle's salt (saturated solution),diluted with DCM and stirred at RT for 20 min. The gel was removed byfiltering through Celite® and the filtrate was separated. The organicphase was dried over Na₂SO₄ and concentrated in vacuo to leave the titlecompound (Intermediate AB84-3) as a mixture of desired product and someproduct with loss of TBS-protecting group (3.01 g). Carried forward intothe next step as a mixture.

Step 3: 6-Bromo-2-((dimethylamino)methyl)pyridin-3-ol (IntermediateAB84-4)

A solution of 6-bromo-3-((tert-butyldimethylsilyl)oxy)picolinaldehyde(Intermediate AB84-3) (3.00 g, 9.49 mmol) and dimethylamine (2M solutionin THF, 9.5 mL, 18.97 mmol) in DCM/MeOH (6:1, 35 mL), with MgSO4 dryingagent added, was treated with sodium triacetoxyborohydride (3.02 g,14.23 mmol). After stirring at RT for 18 h, the reaction mixture wasdry-loaded onto ISOLUTE® HM-N disposable liquid-liquid extractioncolumns and purified by column (gradient elution: 0-10% 7N methanolicammonia in DCM) to afford the title compound (Intermediate AB84-4) (1.14g, 4.94 mmol) as an orange oil. ¹H NMR (400 MHz, CDCl₃): δ 7.24 (d,J=8.7 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 3.84 (s, 2H), 2.38 (s, 6H).

Step 4:(R)-1-(6-Bromo-34(THF-3-yl)oxy)pyridin-2-yl)-N,N-dimethylmethanamine(AB84)

A solution of 6-bromo-2-((dimethylamino)methyl)pyridin-3-ol(Intermediate AB84-4) (350 mg, 1.51 mmol) and (R)-(−)-3-hydroxy-THF (200mg, 2.27 mmol) in THF (10 mL) under a nitrogen atmosphere was treatedwith triphenyl phosphine (675 mg, 2.57 mmol), followed by diethylazodicarboxylate (528 mg, 3.03 mmol) dropwise. After stirring at RT for4 h, a solution of 2N sodium hydroxide was added. After stirring for 30min, the mixture was diluted with water and extracted into EtOAc (2×).The combined extracts were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by column chromatography(gradient elution: 0-10% 7N methanolic ammonia in DCM) to afford anorange oil and then with an Isolute® SCX-2 cartridge eluting with MeOHfollowed by 7N methanolic ammonia in DCM (1:1) to afford the titlecompound (AB84) (370 mg, 1.23 mmol) as a yellow oil. ¹H NMR (400 MHz,CDCl₃): δ 7.32 (d, J=8.5 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H), 4.93 (ddd,J=2.0, 4.2, 8.2 Hz, 1H), 4.04-3.92 (m, 4H), 3.59 (s, 2H), 2.34 (s, 6H),2.32-2.10 (m, 2H).

Synthesis of6-((dimethylamino)methyl)-4-(tetrahydrofuran-3-yl)pyridin-2-amine(Intermediate AB85)

Step 1: methyl 6-(bis(tert-butoxycarbonyl)amino)-4-bromopicolinate(Int-AB85.2)

To a solution of methyl 6-amino-4-bromo-pyridine-2-carboxylate (2.00 g,8.66 mmol, 1.00 eq)-(Int-AB85.1) in THF (60.00 mL) at 0° C. were addedtriethylamine (3.0 mL, 21.6 mmol, 2.50 eq), Di-tert-butyl decarbonate(4.0 mL, 17.3 mmol, 2.00 eq) and DMAP (0.21 g, 1.73 mmol, 0.200 eq).After stirring at 0° C. for 30 min and then at RT 4 h, the solvent wasremoved in vacuo and the crude residue purified by column chromatography(0-5% gradient eluting with 7N methanolic ammonia in DCM) to afford thetitle compound (Int-AB85.2) (3.51 g, 8.13 mmol, 94%) as an off whitesolid. ¹H NMR (400 MHz, DMSO): δ 8.20 (d, J=2.2 Hz, 1H), 8.18 (d, J=2.2Hz, 1H), 3.94 (s, 3H), 1.46 (s, 18H).

Step 2: tert-butyl (4-bromo-6-(hydroxymethyl)pyridin-2-yl)carbamate(Int-AB85.3)

A solution of Int-AB85.2 (3.51 g, 8.13 mmol) in ethanol (80 mL) wastreated portion-wise with sodium borohydride (1.22 g, 32.5 mmol). Afterstirring for 15 min and then stirring at 70° C. for 2 h, the cooledreaction mixture was quenched with dropwise addition of water (30 mL),and the ethanol removed in vacuo. The residue was extracted into EtOAc(3×40 mL). The combined organic phases were washed with brine (20 mL),dried over magnesium sulfate, filtered, and concentrated in vacuo toafford the title compound (Int-AB85.3) (2.34 g, 7.71 mmol, 95%) as ayellow oil. ¹H NMR (400 MHz, DMSO): δ 10.10 (s, 1H), 7.95 (d, J=1.3 Hz,1H), 7.33 (d, J=2.2 Hz, 1H), 5.56 (t, J=5.9 Hz, 1H), 4.50 (d, J=5.7 Hz,2H), 1.51 (s, 9H).

Step 3: tert-butyl(4-bromo-6-((dimethylamino)methyl)pyridin-2-yl)carbamate (Int-AB85.4)

To a solution of Int-AB85.3 (2.34 g, 7.72 mmol) and DIPEA (5.4 mL, 30.9mmol) in acetonitrile (60 mL) at 0° C. was added methanesulfonylchloride (1.2 mL, 15.4 mmol). After stirring for 20 minutes at 0° C. andthen at RT for 1.5 h, the reaction was quenched with water (40 mL) andextracted with ethyl acetate (3×40 mL). The combined organic phases werewashed with brine, passed through a hydrophobic filter, and concentratedin vacuo.

To the residue dissolved in acetonitrile (60 mL) were addeddimethylamine (2M solution in THF, 11.5 mL, 23.157 mmol) and potassiumcarbonate (3.2 g, 23.157 mmol). After stirring at reflux for 3 h, thereaction was cooled, diluted with water (50 mL) and extracted with ethylacetate (3×40 mL). The combined organic phases were dried over magnesiumsulfate, filtered, and concentrated in vacuo. The residue was purifiedby column chromatography (0-20% gradient elution with 7N methanolicammonia in DCM to afford the title compound Int-AB85.4 (1.37 g, 54%) asa brown solid. ¹H NMR (400 MHz, DMSO): δ 10.12 (s, 1H), 7.96 (d, J=1.8Hz, 1H), 7.31 (d, J=1.6 Hz, 1H), 3.46 (s, 2H), 2.24 (s, 6H), 1.51 (s,9H).

Step 4: tert-butyl(4-(2,5-dihydrofuran-3-yl)-6-((dimethylamino)methyl)pyridin-2-yl)carbamate(Int-AB85.5)

To a mixture of Int-AB85.4 (1.37 g, 4.15 mmol) in 1,4-dioxane (25.0 mL)and water (4 mL) were added2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.89g, 4.56 mmol), XPhos-Pd-Gen2 (0.32 g, 0.415 mmol), XPhos (0.20 g, 0.415mmol) and potassium phosphate tribasic (2.64 g, 12.4 mmol). Afterdegassing with nitrogen and stirring at 80° C. for 3 h, the cooledmixture was diluted with water (30 mL) and extracted into EtOAc (3×40mL). The combined extracts were washed with brine (50 mL) dried overmagnesium sulfate, filtered, and concentrated in vacuo. The residue waspurified by column chromatography (0-100% gradient elution with EtOAc incyclohexane followed by 0-10% 7N methanolic ammonia in EtOAc) to affordthe title compound Int-AB85.5 (1.12 g, 3.51 mmol, 85%) as an orange oil.

¹H NMR (400 MHz, DMSO): δ 9.81 (s, 1H), 7.66 (s, 1H), 7.14 (s, 1H), 6.77(t, J=2.0 Hz, 1H), 4.97-4.92 (m, 2H), 4.83-4.77 (m, 2H), 3.45 (s, 2H),2.23 (s, 6H), 1.51 (s, 9H).

Step 5:6-((dimethylamino)methyl)-4-(tetrahydrofuran-3-yl)pyridin-2-amine (AB85)

To a solution of Int-AB85.5 (1.12 g, 3.51 mmol) in methanol (5 mL) andethanol (15 mL) was added 10% palladium on carbon (373 mg, 10 mol %).After stirring under an atmosphere of hydrogen gas at room temperaturefor 16 h, the reaction mixture was filtered through Celite® andconcentrated in vacuo.

To a solution of the reduced product in DCM (15 mL) was added dropwisetrifluoroacetic acid (2.7 mL, 35.1 mmol). After stirring at RT for 3 h,the solvent was removed in vacuo and the crude residue purified byIsolute® SCX-2 cartridge eluting with 0-10% methanol/DCM followed by 10%7N methanolic ammonia in DCM. The residue was purified further by columnchromatography (0-10% gradient elution 7N methanolic ammonia in DCM) toafford the title compound (AB85) (354 mg, 1.59 mmol 45%) as an orangeoil. ¹H NMR (400 MHz, DMSO): δ 6.50 (s, 1H), 6.24 (s, 1H), 5.81 (s, 2H),4.02 (t, J=7.4 Hz, 1H), 3.98-3.92 (m, 1H), 3.84-3.77 (m, 1H), 3.57 (t,J=7.4 Hz, 1H), 3.28 (s, 2H), 3.25-3.22 (m, 1H), 2.35-2.27 (m, 1H), 2.21(s, 6H), 1.94-1.87 (m, 1H).

The following intermediates were available commercially or prepared byknown literature routes.

TABLE 3 Additional intermediates that were commercially available orprepared by known literature routes. # STRUCTURE AC8

AC9

AC10

AC11

AC12

AC14

AC15

AC16

AC17

AC18

AC19

AC21

AC22

AC23

AC24

AC25

AC26

AC27

AC32

AC35

AC38

AC44

AC49

The following intermediates were prepared according to IntermediateMethods A1 to M1 as described above.

TABLE 4 Intermediates prepared according to Intermediate Methods A1 toM1. # STRUCTURE Method AC1

Method A1 using (R)- tert-butyl- methyl (piperidin-3- yl)carbamate AC2

Method B1 using tert- butyl methyl(4- methyl- piperidin-4- yl)carbamateAC3

Method C1 using (R)-1- (piperidin-4- yl)ethanol AC4

Method D1 using ethylamine AC5

Method E1 using tert- butyl methyl(4- piperidinyl) carbamate AC6

Method F1 using tert- butyl-(S)- methyl(pyrrol- idin-3-yl) carbamate AC7

Method G1 using N,N,N′- trimethylethyl enediamine AC13

Method A1 using tert- butyl methyl(4- piperidinyl) carbamate AC20

Method A1 using (S)-tert- butyl- methyl (piperidin-3- yl)carbamate AC28

Method E1 using 4- hydroxy- piperidine AC29

Method C1 using (R)-2- (piperidin-3- yl)propan-2-ol AC30

Method C1 using (S)-2- (piperidin- 3-yl)propan- 2-ol AC31

Method C1 using tert- butyl piperidine-4- carboxylate AC33

Method C1 using 2- (piperidin- 4-yl)propan- 2-ol AC34

Method D1 using N,N- dimethylethyl enediamine AC36

Method E1 using tert- butyl (R)- piperidin-3- ylcarbamate AC37

Method E1 using tert- butyl (R)- piperidin-3- ylcarbamate AC39

Method A1 using 2- methoxy-N- methylethan- 1-amine AC40

Method E1 using tert- butyl (R)- methyl (piperidin-3- yl)carbamate AC41

Method F1 using tert- butyl 1,4- diazepane-1- carboxylate AC42

synthesis of Intermediate AA49 using trans-4- fluoro-3- hydroxy-piperidine AC43

Method F1 using tert- butyl azetidine-3- yl(methyl) carbamatehydrochloride AC45

Method A1 using (S)- morpholin-2- ylmethanol AC46

Method A1 using (R)-2- (morpholin- 2-yl)propan- 2-ol AC47

Method A1 using (S)-2- (morpholin-2- yl)propan-2- ol AC48

Method H1 using 4- (Boc- amino)-3,3- difluoro- piperidine AC50

Method I1 Using dimethylamine AC51

Method F1 using tert- butyl hexahydro- pyrrolo[3,4- AC52

Method A1 using 4- (piperidin-3- yl) morpholine AC53

Method J1 using cyclopropyl amine AC54

Method F1 using (3aR,6aR)- tert-butyl hexahydro- pyrrolo[3,4- b]pyrrole-5(1H)- carboxylate AC55

Method J1 using 3- fluoroazetidine AC56

Method A1 using 4- (piperidin-4- yl)morpholine AC57

Method K1 using (S)-3- fluoro- pyrrolidine hydrochloride AC58

Method K1 using N- methylcyclo- propanamine AC59

Method K1 using 3- fluoroazetidine hydrochloride AC60

Method J1 using N- methylcyclo- propanamine AC61

Method J1 using cyclopropan amine AC62

Method F1 using (3aS,6aS)- tert-butyl hexahydro- pyrrolo[3,4- b]pyrrole-5(1H)- carboxylate AC63

Method A1 using 4- methyl-1- oxa-4 8- diazaspiro[5.5] undecane AC64

Method J1 using N- methylcyclo- propanamine AC65

Method A1 using 4- Boc-1-oxa- 4,8- diazaspiro[5.5] undecane AC66

Method I1 using diethylamine AC67

Method I1 using pyrrolidine AC68

Method A1 using N,N- dimethyl-1,4- oxazepan-6- amine AC69

Method A1 using N,N- dimethyl(3- morpholinyl) methanamine AC70

Method J1 using imidazole AC71

Method L1 using (S)- piperidin-3-ol AC72

Method A1, Step 1 using (3-fluoro- piperidin-3- yl) methanol followed byMethod J1 using dimethylamine AC73

Method L1 using dimethylamine AC74

Method L1 using (S)-2- methyl- morpholine AC75

See synthesis procedure for Intermediate AA144 using (R)- piperidin-3-olAC76

See synthesis procedure for Intermediate AA144 using 7-oxa-4-azaspiro[2.5] octane AC77

Method L1 using 4- hydroxy- piperidine AC78

See synthesis procedure for Intermediate AA144 using (R)-3-methyl-morpholine AC79

See synthesis procedure for Intermediate AA144 using (S)-2- methyl-morpholine AC80

See synthesis procedure for Intermediate AA144 using 4-oxa-7-azaspiro[2.5] octane AC81

See synthesis procedure for Intermediate AA144 using (S)-3- methyl-morpholine AC82

See synthesis procedure for Intermediate AA144 using (S)-piperidin- 3-olAC83

See synthesis procedure for Intermediate AA144 using 4- methyl-1,4-diazepan-5- one AC84

Method M1 using (R)-(−)- 3-hydroxy- THF AC85

See synthesis procedure for Intermediate AA144 using 4- methyl-piperidin-4-ol AC86

Method I1, step 3 using 2-Chloro- 5,6,7,8- tetrahydro- quinolin-8-olAC87

See synthesis procedure for Intermediate AA144 using (R)-2- methyl-morpholine AC88

Method M1 using (S)-(−)- 3-hydroxy- THF AC89

Method I1 using 3- methoxy- azetidine AC90

Method I1 using 2-(5,6- dihydro-2H- pyran-3-yl)- 4,4,5,5- tetramethyl-1,3,2- dioxaborolane AC91

Method M1 using tetrahydro- 2H-pyran-4-ol AC92

Method I1 using tributyl(4,5- dihydrofuran- 2-yl)stannane (step 4 wasperformed following protocol described in WO2013086397) AC93

See synthesis procedure for Intermediate AA144 using (S)- pyrrolidin-3-ol AC94

Method I1 using 1- Methyl-4- (4,4,5,5- tetramethyl- 1,3,2- dioxaborolan-2-yl)-1,2,5,6- tetrahydro- pyridin-2-one AC95

See synthesis procedure for Intermediate AA157 using propan-2- amineAC96

See synthesis procedure for Intermediate AA157 using propan-2- amine and3,4-dihydro- 2H-pyran-5- ylboronic acid, pinacol ester AC97

Method I1 using 3,4- dihydro-2H- pyran-5- ylboronic acid, pinacol esterAC98

See synthesis procedure for Intermediate AA157 using 2- methylpropan-2-amine AC99

See synthesis procedure for Intermediate AA157 using cyclopropylmethanamine AC100

See synthesis procedure for Intermediate AA144 using 4-(methoxy- methyl)piperidin- 4-ol

Synthesis of tert-butyl2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(Intermediate BB11)

Step-1 Synthesis of tert-butyl3-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (IntermediateBB11-2)

To a solution of Intermediate BB11-1 (1.5 g, 7.11 mmol) in DCM (15 mL)were added trimethylamine (2.154 g, 21.32 mmol, 3.0 eq), N,N-DMAP (0.086g, 0.71 mmol, 0.1 eq) and Boc-anhydride (2.324 g, 10.66 mmol, 1.5 eq) atRT. After stirring at RT for 1 h, the reaction mixture was poured intoice cold water (200 mL) and extracted with ethyl acetate (100 mL×3). Thecombined organic layer was dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified by columnchromatography eluting with 15% ethyl acetate in hexane to affordIntermediate BB11-2 (1.6 g, 72.35%). MS (ES): m/z 312.15[M+H]⁺

Step-2 Synthesis of tert-butyl2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(Intermediate BB11)

To a solution of Intermediate BB11-2 (1.0 g, 3.21 mmol) and4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi-(1,3,2-dioxaborolane) (1.8 g,7.06 mmol, 2.2 eq) in 1,4-dioxane (10 mL) was added potassium acetate(0.63 g, 6.42 mmol, 2.0 eq) at RT. After degassing using argon gas for20 mins, tris(dibenzylideneacetone)dipalladium(O) (0.147 g, 0.16 mmol,0.05 eq) and tricyclohexylphosphine (0.1 g, 0.38 mmol, 0.12 eq) wereadded to the reaction mixture. After stirring at 110° C. for 16 h, thereaction mixture was poured into water (100 mL) and extracted with ethylacetate (100 mL×3). The combined organic layer was washed with brinesolution (100 mL), dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with 50% ethyl acetate in hexane to afford Intermediate BB11(1.0 g, quantitative yield). MS (ES): m/z 359.39 [M+H]⁺.

Synthesis of tert-butyl6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(Intermediate BB12)

Step-1 Synthesis of 3-bromo-6-methyl-1H-pyrrolo[2,3-b]pyridine(Intermediate BB12-2)

To a solution of Intermediate BB12-2 (1.0 g, 7.57 mmol) in THF (10 mL)were added N-bromosuccinimide (2.021 g, 11.35 mmol, 1.5 eq) and thenhydrochloric acid at RT. After stirring at RT for 2 days, the reactionmixture was neutralized using saturated sodium bicarbonate (100 mL) andextracted with ethyl acetate (100×3). The combined organic layer wasdried over sodium sulfate and concentrated under reduced pressure toafford crude material. The residue was purified by column chromatographyeluting with 35% ethyl acetate in hexane to afford Intermediate BB12-2(1.5 g, 93.93%), MS (ES): m/z 211.75[M+H]⁺.

Step-2, 3 Synthesis of tert-butyl6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(Intermediate BB12)

tert-butyl6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(Intermediate BB12) was prepared from3-bromo-6-methyl-1H-pyrrolo[2,3-b]pyridine (Intermediate BB12-2) in asimilar fashion to that described in tert-butyl2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(General process intermediate BB11). (0.750 g, quantitative yield). MS(ES): m/z 359.74[M+H]⁺

Synthesis of tert-butyl2,6-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(Intermediate BB13)

Step-1 Synthesis of 3-bromo-2,6-dimethyl-1H-pyrrolo[2,3-b]pyridine(Intermediate BB13-2)

To a solution of Intermediate BB13-1 (5.0 g, 34.240 mmol) intert-butanol (200 mL) was added pyridinium tribromide (12.0 g, 37.670mmol, 1.1 eq) at RT. After stirring for 4 h, the reaction mixture wasquenched with water (500 mL) and extracted with ethyl acetate (250mL×3). The combined organic layer was washed with brine solution (300mL), dried over sodium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography eluting with 50% ethylacetate in hexane to afford Intermediate BB13-2 (6.7 g, 87.63%) MS (ES):m/z 227 [M+2]⁺

Step-2 3 Synthesis of tert-butyl2,6-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(Intermediate BB13)

tert-butyl2,6-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(Intermediate BB13) was prepared from2,6-dimethyl-1H-pyrrolo[2,3-b]pyridine (Intermediate BB13-1) in asimilar fashion to that described in tert-butyl6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(General process intermediate BB12). (0.16 g, 46.59%). MS (ES):71% m/z191.5[M-100]⁺(Boronic ester)+25% m/z 317.7 [M-56]⁺(Boronic acid).

Synthesis of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(Intermediate BB14)

Step 1 Synthesis of 4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine(Intermediate BB14-2)

To a solution of 60% sodium hydride (8.12 g, 0.2030 mol, 2.0 eq) in DMF(100 mL) at 0° C. under nitrogen was added a solution of IntermediateBB14-1 (20.0 g, 0.0473 mol) in DMF (50 mL). After stirring at 0° C. for30 min, methyl iodide (7.58 mL, 0.121 mol, 1.2 eq) was added. Afterstirring at RT for 30 min, the reaction mixture was poured into an icecold water and extracted with ethyl acetate (300 mL×3). The combinedorganic layers were dried over sodium sulfate and concentrated underreduced pressure to afford Intermediate BB14-2 (20 g, quantitativeyield). MS (ES): m/z 211.50 [M+H]⁺. ¹H NMR (400 MHz, DMSO): δ 8.15 (d,1H), 7.67 (d, 1H), 7.38 (d, 1H), 6.45 (d, 1H), 3.90 (s, 3H).

Step 2 Synthesis of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(Intermediate BB14)

To a solution of Intermediate BB14-2 (10.0 g, 0.047 mol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-(1,3,2-dioxaborolane) (11.99 g,0.0473 mol) in 1,4-dioxane (100 mL) was added potassium acetate (13.09g, 0.141 mol, 3.0 eq) at RT. After degassing with argon gas for 20 min,[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II) DCM complex(3.85 g, 3.85 mol, 0.1 eq) was added. After stirring at 90° C. for 2.5h, the reaction mixture was poured into water and extracted with ethylacetate (250 mL×3). The combined organic layer washed with brinesolution, dried over sodium sulfate, and concentrated under reducedpressure to afford crude material. The residue was purified via columnchromatography eluting with 15% ethyl acetate in hexane to affordIntermediate BB14 (10.5 g, 82%). m/z 258.5 (M+H)⁺¹H NMR (400 MHz, DMSO):δ 8.32 (d, 1H), 7.61 (d, 1H), 7.36 (d, 1H), 6.71 (d, 1H), 3.87 (s, 3H),1.39 (m, 12H).

Synthesis of tert-butyl3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(Intermediate BB15)

tert-butyl3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(Intermediate BB15) was prepared from4-bromo-3-methyl-1H-pyrrolo[2,3-b]pyridine (Intermediate BB15-1) in asimilar fashion to that described in tert-butyl2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(Intermediate BB11). (0.165 g, 19.85%). MS (ES): m/z 359.4[M+H]⁺.

Synthesis of tert-butyl3-(tributylstannyl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(Intermediate BB38)

Step-1 Synthesis of tert-butyl3-bromo-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (Intermediate BB38-2)

tert-butyl 3-bromo-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (IntermediateBB38-2) was prepared from 3-bromo-1H-pyrrolo[2,3-c]pyridine(Intermediate BB38-1) in a similar fashion to that described intert-butyl 3-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(General process Intermediate BB11-2). (0.7 g, 61.56%). (4 g, 75%). MS(ES): m/z 237.15 [M+H]⁺

Step-2 Synthesis of tert-butyl3-(tributylstannyl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(Intermediate BB38)

To a solution of Intermediate BB38-2 (0.5 g, 1.79 mmol) in THF (10 mL)was added n-butyllithium solution (0.8 mL, 1.97 mmol, 1.1 eq) at −78° C.under argon. After stirring for 20 mins, tributyltin chloride (0.58 g,1.79 mmol) was added. After stirring at −78° C. for 10 min, the reactionmixture was quenched with saturated NH₄C1 solution (100 mL) andextracted with ethyl acetate (100 mL×3). The combined organic layerswere washed with brine solution (100 mL), dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 2-5% ethyl acetate in hexane to affordIntermediate BB38 (0.25 g, 29.29%). MS (ES): m/z 507.9[M+H]⁺.

Synthesis of tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(Intermediate BB44)

tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(Intermediate BB44) was prepared from2,6-dimethyl-1H-pyrrolo[2,3-b]pyridine (Intermediate BB44-1) in asimilar fashion to that described in tert-butyl2,6-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(General process Intermediate BB13). (0.16 g, 46.59%). MS (ES):71% m/z191.5[M-100]⁺(Boronic ester)+25% m/z 317.7 [M-56]⁺(Boronic acid).

Synthesis of tert-butyl6-(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate(Intermediate BB50)

Step-1 Synthesis of 6-(benzyloxy)-3-bromo-1H-indole (IntermediateBB50-2)

To a solution of Intermediate BB50-1 (3.0 g 13.4 mmol, 1.0 eq.) in DMF(25.0 mL) was added bromine (2.57 g, 16.1 mmol, 1.2 eq.) at 0° C. Afterstirring at RT for 1 h, the reaction mixture was poured into water (100mL) and extracted with ethyl acetate (100 mL×3). The combined organiclayers were washed with brine (100 mL) solution, dried over sodiumsulfate, and concentrated under reduced pressure 25° C. to affordIntermediate BB50-2 (2 g, 49.2%). MS (ES): m/z 302 (M+H)⁺

Step-2, 3 Synthesis of tert-butyl6-(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate(Intermediate BB50)

tert-butyl 6-(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate(Intermediate BB50) was prepared from 6-(benzyloxy)-3-bromo-1H-indole(Intermediate BB50-2) in a similar fashion to that described intert-butyl2,6-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(General process Intermediate BB13). (0.450 g, 49.2%). MS (ES): m/z 449(M+H)⁺.

Synthesis 2-(4-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)acetamide(Intermediate BB55)

Step-1 Synthesis of2-(4-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)acetonitrile (IntermediateBB55-2)

To a solution of Intermediate BB55-1 (2.0 g 10.1 mmol, 1.0 eq.) in DMF(15.0 mL) were added sodium hydride (0.49 g 20.3 mmol, 2.0 eq.) at 0° C.After stirring at RT for 20 mins, 2-iodoacetonitrile (2.3 g, 12.1 mmol,1.5 eq.) was added. After stirring at RT for 1 h, the reaction mixturewas poured into water (100 mL) and extracted with ethyl acetate (100mL×3). The combined organic layer was washed with brine (100 mL)solution, dried over sodium sulfate, and concentrated under reducedpressure to afford Intermediate BB55-2 (1.7 g, 70.9%). MS (ES): m/z 236(M+H)⁺.

Step-2 Synthesis of 2-(4-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)acetamide(Intermediate BB55)

To a solution of Intermediate BB55-2 (1.5 g 6.3 mmol, 1.0 eq.) indimethyl sulfoxide (15.0 mL) were added potassium carbonate (2.6 g, 19.0mmol, 3.0 eq.). After stirring at 60° C. for 20 min, hydrogen peroxide(1.08 g, 31.7 mmol, 5.0 eq.) was added. After stirring at 60° C. for 20min, the reaction mixture was poured into water (100 mL) and extractedwith ethyl acetate (100 mL×3). The combined organic layer was washedwith brine (100 mL) solution, dried over sodium sulfate, andconcentrated under reduced pressure to afford Intermediate BB55 (1.7 g,105.30%). MS (ES): m/z 254 (M+H)⁺.

Synthesis of 7-bromooxazolo[5,4-b]pyridine (Intermediate BB56)

Step-1 Synthesis of oxazolo[5,4-b]pyridin-7-ol (Intermediate BB56-2)

Prepared as described in WO2016106106.

Step-2 Synthesis of 7-bromooxazolo[5,4-b]pyridine (Intermediate BB56)

To a solution Intermediate BB56-2 (0.130 g, 0.95 mmol) in DMF (2 mL) wasadded phosphoryl bromide (0.320 g, 1.14 mmol, 1.2 eq) at 0° C. Afterstirring at 100° C. for 2 h, the reaction mixture was quenched withsodium bicarbonate solution in water (100 mL) and extracted into ethylacetate (100 mL×3). The combined organic layers were washed with brinesolution (100 mL), dried over sodium sulfate and concentrated underreduced pressure. The residue was purified using combi-flash silicaeluting with 1-2% methanol in DCM to afford Intermediate BB56 (0.150 g,78.92%) MS (ES): m/z 199.94 [M+H]⁺

Synthesis of 3-iodo-7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine(Intermediate BB62)

Step-1 Synthesis of3-iodo-7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (IntermediateBB62)

To a solution of Intermediate BB62-1 (1.8 gm, 1.32 mmol, 1 eq) inacetonitrile was added N-Iodosuccinimide (3.8 gm, 41.8 mmol, 5 eq).After stirring at RT for 90 min, the reaction mixture was poured intowater (100 mL) and extracted with ethyl acetate (100 mL×3). The combinedorganic layer was washed with brine (100 mL) solution, dried over sodiumsulfate, and concentrated under reduced pressure to afford IntermediateBB62. (0.700 gm, 20.21%): m/z 263.03 [M+H]⁺

Synthesis of 7-fluoro-3-iodoimidazo[1,2-a]pyridine (Intermediate BB63)

Step-1 Synthesis of 7-fluoroimidazo[1,2-a]pyridine (Intermediate BB63-2)

To a solution of 4-fluoropyridin-2-amine (50 g, 0.44 mol) in ethanol(450 mL) was added chloro acetaldehyde (50% in Water) (300 mL, 6 vol)and sodium bicarbonate (74.9 g, 0.89 mol, 2.0 eq). After stirring at 60°C. for 4 h, the reaction mixture was concentrated under vacuum. Thecrude material was purified via column chromatography eluting with 35%ethyl acetate in hexane to afford Intermediate BB63-2 (50 g, 82.35%) MS(ES): m/z 137.16 [M+H]⁺, 1H NMR (400 MHz, DMSO): δ 8.62 (t, 1H), 7.93(s, 1H), 7.54 (s, 1H), 7.39 (d, 1H), 6.96 (t, 1H).

Step-2 Synthesis of 7-fluoro-3-iodoimidazo[1,2-a]pyridine (IntermediateBB63)

To a solution 7-fluoroimidazo[1,2-a]pyridine (28 g, 0.20 mol) inchloroform (300 mL) was added N-iodosuccinimide (50.65. g, 0.22 mol, 1.1eq). After stirring at RT for 3 h, the reaction mixture was quenchedwith solution of sodium thiosulfate (1000 mL) and extracted with ethylacetate (600 mL×3). The combined organic solution was dried over sodiumsulfate and concentrated in vacuum. The crude material was purified viacolumn chromatography eluting with 18% ethyl acetate in hexane to affordIntermediate BB63. (30 g, 56.6%) MS (ES): m/z 262.94 [M+H]⁺ 1H NMR (400MHz, DMSO): δ 7.11 (m, 1H), 7.54 (d, 1H), 7.69 (s, 1H), 8.36-8.39 (t,1H).

Synthesis of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine(Intermediate BB68)

To a solution of the 4-bromopyrazolo[1,5-a]pyridine Intermediate(BB68-1) (0.25 g, 1.27 mmol) in 1-4 dioxane (580 mL) were addedbis(pinacolato)diboron (0.991 g, 3.83 mmol, 3.0 eq) and potassiumacetate (0.375 g, 3.83 mmol, 3.0 eq). After degassing with flow of argonfor 20 min, XPhos Pd G2 (0.05 g, 0.063 mmol, 0.05 eq) was added andagain degassed for 10 min. After stirring at 100° C. for 2 h, thereaction was cooled to RT, filtered through celite, and washed withethyl acetate (50 mL×3). The combined organic layer was washed withWater (50 mL), dried over Na₂SO₄, and concentrated under reducedpressure. The residue was purified by silica gel chromatography elutingwith 2.0% MeOH/DCM to afford Intermediate BB68 (0.2 g, 64%). MS (ES):m/z 245.3 [M+H]⁺.

Synthesis of 5-iodo-7-methyl-711-pyrrolo[2,3-c]pyridazine (IntermediateBB69), 5-iodo-7-methyl-711-pyrrolo[2,3-c]pyridazine (Intermediate BB70)and 5-iodo-2-methyl-2H-pyrrolo[2,3-c]pyridazine ((Intermediate BB78)

5-iodo-7-methyl-7H-pyrrolo[2,3-c]pyridazine (Intermediate BB69) and5-iodo-7-methyl-7H-pyrrolo[2,3-c]pyridazine (Intermediate BB70) wasprepared from 7H-pyrrolo[2,3-c]pyridazine in a similar fashion to thatdescribed in 3-iodo-6-methyl-6H-pyrrolo[2,3-d]pyridazine (IntermediateBB43). Intermediate BB69 (0.1 g, 20%). MS (ES): m/z 260.1 (M+H)⁺.Intermediate BB70 (0.05 g, 10%). MS (ES): m/z 260.1 (M+H)⁺. IntermediateBB78 (0.1 g, 20%). MS (ES): m/z 260.1 (M+H)⁺.

Synthesis of7-((3-fluoroazetidin-1-yl)methyl)-3-iodoimidazo[1,2-a]pyridine(Intermediate BB71)

Step-1 Synthesis of imidazo[1,2-a]pyridine-7-carbaldehyde (IntermediateBB71-2)

To a solution of imidazo[1,2-a]pyridine-7-carbaldehyde (1 g, 6.84 mmol)in methanol (10 mL) was added 3-fluoroazetidine hydrochloride (2.3 g,20.5 mmol, 3.0 eq), trimethylamine (2 mL, 13.6 mol, 2.0 eq) at 0° C. andstirred for 15 min. Sodium cyanoborohydride (5.8 g, 27.3 mol, 4.0 eq)was added portion wise. After stirring at rt for 16 h, the reactionmixture was quenched with water (100 mL) and extracted with ethylacetate (50 mL×3). The combined organic layers were dried over sodiumsulfate and concentrated on vacuum. The crude material purified viacolumn chromatography eluting with 40% ethyl acetate in hexane to affordIntermediate BB71-2 (1.1 g, 78%) MS (ES): m/z 206.16 [M+H]⁺.

Step-2 Synthesis of7-((3-fluoroazetidin-1-yl)methyl)-3-iodoimidazo[1,2-a]pyridine(Intermediate BB71)

7-((3-fluoroazetidin-1-yl)methyl)-3-iodoimidazo[1,2-a]pyridine(Intermediate BB71) was prepared from7-((3-fluoroazetidin-1-yl)methyl)imidazo[1,2-a]pyridine in a similarfashion to that described in 7-fluoro-3-iodoimidazo[1,2-a]pyridine(General process Intermediate BB63). (0.8 g, 60%). MS (ES): m/z 332(M+H)⁺.

Synthesis of1-(3-iodoimidazo[1,2-a]pyridin-7-yl)-N,N-dimethylmethanamine(Intermediate BB72)

1-(3-iodoimidazo[1,2-a]pyridin-7-yl)-N,N-dimethylmethanamine(Intermediate BB72) was prepared fromimidazo[1,2-a]pyridine-7-carbaldehyde in a similar fashion to thatdescribed in7-((3-fluoroazetidin-1-yl)methyl)-3-iodoimidazo[1,2-a]pyridine(Intermediate BB71) (General process Intermediate BB71). (0.7 g, 60%).MS (ES): m/z 302.6 (M+H)⁺.

Synthesis of 3-iodo-7-(1-methylazetidin-3-yl)imidazo[1,2-a]pyridine(Intermediate-BB75)

Step-1 Synthesis of tert-butyl3-(2-chloropyridin-4-yl)azetidine-1-carboxylate (Intermediate BB75-2)

To a degassed solution of Zn dust (9.5 g, 147.03 mmol, 3.5 eq) indimethylacetamide (50 mL) were added dropwise trimethylsilyl chloride(1.3 mL, 10.50 mmol, 0.25 eq) and 1,2 dibromoethane (1.57 g, 8.40 mmol,0.2 eq). In a separate flask, to a degassed of mixture [1,1′- ofbis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with DCM(6.8 g, 8.40 mmol, 0.2 eq) and Copper(I) iodide (1.6 g, 8.40 mmol, 0.2eq) was added a solution of Intermediate BB75-1 (10 g, 42.01 mmol) indimethylacetamide (50 mL). After stirring at RT for 15 min, bothreaction mixtures were mixed. After stirring at 80° C. for 2 h, thereaction mixture was cooled at RT, diluted with water (500 mL), andextracted with ethyl acetate (3×200 mL). The combined organic extractswere washed with brine (300 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 10% ethyl acetate gradient in hexane toafford Intermediate BB75-2 (6.0 g, 53.46%), MS (ES): m/z=269.2 [M+H]⁺

Step-2 Synthesis of tert-butyl3-(2-(cyclopropanecarboxamido)pyridin-4-yl)azetidine-1-carboxylate(Intermediate BB75-3)

A solution of Intermediate BB75-2 (6.0 g, 22.38 mmol) andcyclopropanecarboxamide (2.2 g, 26.85 mmol, 1.2 eq), Cs₂CO₃ (14.5 g,44.76 mmol, 2.0 eq) in 1,4-Dioxane (50 mL) was degassed under N2 stream.After 15 min, Xantphos (1.3 g, 2.23 mmol, 0.1 eq) and Pd₂(dba)₃ (1.0 g,1.11 mmol, 0.05 eq) were added. After stirring at 100° C. for 16 h, thereaction mixture was cooled to RT, diluted with water (200 mL), andextracted with ethyl acetate (3×100 mL). The combined organic extractswere washed with brine (200 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 30% ethyl acetate gradient in hexane toafford Intermediate BB75-3 (5.0 g, 70.56%). MS (ES): m/z=318.2 [M+H]⁺

Step-3 Synthesis of tert-butyl3-(2-aminopyridin-4-yl)azetidine-1-carboxylate (Intermediate BB75-4)

To a solution of Intermediate BB75-3 (5.0 g, 15.77 mmol) in methanol (50mL) and water (15 mL) was added sodium hydroxide (6.3 g, 157.7 mmol,10.0 eq). After stirring 4 h at 80° C., the reaction mixture was dilutedwith ice cold water (100 mL) and extracted with ethyl acetate (3×50 mL).The combined organic extracts were washed with brine (100 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure to affordcrude material which was used in next Step without purification.Intermediate BB75-4 (5.0 g, quantitative %), MS (ES): m/z=250.3 [M+H]⁺

Step-4 Synthesis of tert-butyl3-(imidazo[1,2-a]pyridin-7-yl)azetidine-1-carboxylate (IntermediateBB75-5)

To a solution of Intermediate BB75-4 (5.0 g, 20.08 mmol) in ethanol (50mL) was added aqueous sodium bicarbonate (3.4 g, 40.16 mmol, 2.0 eq).After stirring for 10 min at RT, chloroacetaldehyde (55% solution inwater) (2.0 g, 26.10 mmol, 1.3 eq) was added into the reaction mixture.After stirring at 80° C. for 2 h, the reaction mixture was diluted withice cold water (80 mL) and extracted with ethyl acetate (3×40 mL). Thecombined organic extracts were washed with brine (100 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure to affordcrude material which was used in next Step without purification.Intermediate BB75-5 (2.5 g, 45.61%), MS (ES): m/z=274.1 [M+H]⁺

Step-5 Synthesis of 7-(azetidin-3-yl)imidazo[1,2-a]pyridine(Intermediate BB75-6)

To a solution of Intermediate BB75-5 (2.5 g, 9.15 mmol,1.0 eq) in DCM:methanol (25 mL:8 mL) at 0° C. was added 4M HCl in dioxane (25 mL).After stirring for 12 h at RT, the reaction mixture was concentratedunder reduced pressure. The residue was dissolved in DCM, diluted withsodium carbonate solution (20 mL) and stirred at RT for 2 h. The organiclayer was concentrated under reduced pressure to afford crude materialwhich was used in next Step without purification. Intermediate BB75-6(1.9 g, quantitative %), MS (ES): m/z=174.2 [M+H]⁺

Step-6 Synthesis of 7-(1-methylazetidin-3-yl)imidazo[1,2-a]pyridine(Intermediate BB75-7)

To a solution of Intermediate BB75-6 (1.9 g, 10.98 mmol) in methanol (20mL) was added formaldehyde (0.4 g, 13.17 mmol, 1.2 eq). After stirringfor 30 min at RT, acetic acid (0.15 mL 2.74 mmol, 0.25 eq) and sodiumborocyanohydride (0.827 g, 13.17 mmol, 1.2 eq) were added into thereaction mixture. After stirring at 50° C. for 16 h, the reactionmixture was cooled to RT, neutralized with NaHCO₃ solution, andextracted with ethyl acetate (3×60 mL). The combined organic extractswere washed with brine (100 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford crude material which wasused in next Step without purification. Intermediate BB75-7 (1.2 g,58.43%), MS (ES): m/z=188.2 [M+H]⁺

Step-7 Synthesis of3-iodo-7-(1-methylazetidin-3-yl)imidazo[1,2-a]pyridine (IntermediateBB75)

To a solution of Intermediate BB75-7 (1.2 g, 6.41 mmol) in chloroform(60 mL) was added portion wise N-Iodosuccinimide (1.7 g, 7.69 mmol, 1.2eq). After stirring for 1 h at RT, the reaction mixture was concentratedunder reduced pressure. The residue was purified by columnchromatography eluting with 10% methanol gradient in DCM (1.0%hydroxylamine) to afford Intermediate BB75 (0.7 g, 34.88%) as a yellowcrystalline solid. MS (ES): m/z=314.2 [M+H]⁺

Synthesis of 3-iodo-6-methyl-611-pyrrolo[2,3-d]pyridazine (IntermediateBB43),3-iodo-5-methyl-511-pyrrolo[2,3-d]pyridazine (Intermediate BB76)and 3-iodo-1-methyl-1H-pyrrolo[2,3-d]pyridazine (Intermediate BB77)

Step-1 Synthesis of Synthesis of 3-iodo-1H-pyrrolo[2,3-d]pyridazine(Intermediate BB43-2)

To a solution of Intermediate BB43-1 (0.98 g 8.22 mmol, 1.0 eq.) in DMF(13.0 mL) at 0° C. was added N-Iodosuccinimide (2.3 g, 9.04 mmol,1.1eq.). After stirring at RT for 1 h, the reaction mixture was poured intowater (50 mL) and extracted using ethyl acetate (50 mL×3). The combinedorganic layer was wash with brine (40 mL) solution and concentratedunder reduced pressure at 45° C. to afford Intermediate-BB43-2 (1.8 gm,48.15%), MS (ES): m/z 246.3.[M+H]⁺, LCMS purity 95%.

Step-2 Synthesis of 3-iodo-6-methyl-611-pyrrolo[2,3-d]pyridazine(Intermediate BB43), 3-iodo-5-methyl-511-pyrrolo[2,3-d]pyridazine(Intermediate BB76) and 3-iodo-1-methyl-1H-pyrrolo[2,3-d]pyridazine(Intermediate BB77)

To a solution of Intermediate BB43-2 (0.8 g 3.2 mmol, 1.0 eq.) andCS₂CO₃ (3.1 g, 9.72 mmol, 3 eq.) in DMF (13.0 mL) was added methyliodide (0.92 g, 6.53 mmol, 2 eq.) in DMF (1 mL) dropwise. After stirringat RT for 30 min, the reaction mixture was poured into water (60 mL) andextracted using ethyl acetate (30 mL×3). The organic layer was wash withbrine (40 mL) solution and concentrated under reduced pressure at 45° C.to afford crude material. The residue was purified by columnchromatography eluting with 7% MeOH in DCM to afford Intermediate BB43.(110 mg, LCMS: 95%, MS (ES): m/z 259.2 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6)δ 8.53 (d, J=5.2 Hz, 1H), 8.14 (s, 1H), 8.94 (d, J=4.8 Hz, 1H), 4.51 (s,3H). Intermediate BB76 (80 mg, LCMS: 97%, MS (ES): m/z 259.5 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d6) δ 8.61 (d, J=5.1 Hz, 1H), 8.46 (s, 1H), 8.75 (d,J=4.9 Hz, 1H), 4.42 (s, 3H). Intermediate BB77 (70 mg, LCMS: 95%, MS(ES): m/z 259.2 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J=5.5 Hz,1H), 8.10 (s, 1H), 8.98 (d, J=4.9 Hz, 1H), 4.56 (s, 3H).

Synthesis of 7-fluoro-3-iodo-8-methylimidazo[1,2-a]pyridine(Intermediate BB80)

7-fluoro-3-iodo-8-methylimidazo[1,2-a]pyridine (Intermediate BB80) wasprepared from 4-fluoro-3-methylpyridin-2-amine in a similar fashion tothat described in 7-fluoro-3-iodoimidazo[1,2-a]pyridine (General processIntermediate BB63). (0.7 g, 60%). MS (ES): m/z 276.6 (M+H)⁺.

Synthesis of8-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine(Intermediate BB81)

Step-1 Synthesis of 7-fluoro-3-bromoimidazo[1,2-a]pyridine (IntermediateBB63-1)

To a solution 7-fluoroimidazo[1,2-a]pyridine (20 g, 0.147 mol) in DCM(200 mL) was added N-bromosuccinimide (28.7. g, 0.161 mol, 1.1 eq).After stirring at RT for 30 min, the reaction mixture was quenched withsolution of sodium thiosulfate (1000 mL) and extracted with DCM (600mL×3). The combined organic washes were dried over sodium sulfate andconcentrated on vacuum. The residue was purified via columnchromatography eluting with 15% ethyl acetate in hexane to affordIntermediate BB81-1. (15 g, 48%) MS (ES): m/z 215.5 217.3 [M]⁺, [M+2]⁺1HNMR (400 MHz, DMSO): δ 7.11 (m, 1H), 7.54 (d, 1H), 7.69 (s, 1H),8.36-8.39 (t, 1H).

Step-2 Synthesis of7-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine(Intermediate BB81)

To a solution of 3-bromo-7-fluoroimidazo[1,2-a]pyridine (0.5 g, 2.32mmol) and isopropoxy boronic acid pinacol ester (1.3 g, 6.97 mmol, 3.0eq) in THF (10 mL) at 0° C. was added dropwise iso-propyl magnesiumchloride lithium chloride complex (3.4 mL, 4.65 mmol, 2.0 eq). Afterstirring at 0° C. for 2 h, the reaction mixture was diluted with water(25 mL) and extracted with ethyl acetate (10 mL×3). The combined organiclayer was dried over sodium sulfate and concentrated under reducedpressure to afford Intermediate BB81 (0.25 g, 59.75%). MS (ES): m/z 180[M+1]⁺ which was used for next step without further purification.

Synthesis of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (IntermediateBB82)

Step-1 Synthesis of 8-bromo-6-chloroimidazo[1,2-b]pyridazine(Intermediate BB82)

To a solution of Intermediate-BB82-1 (1.2 g 5.7 mmol, 1.0 eq.) inisopropyl alcohol (13.0 mL) were added 2-chloro-1,1-diethoxyethane (1.05g, 6.9 mmol,1.2 eq.) and p-toluenesulphonic acid (1.3 g,6.9 mmol,1.2eq.) at RT. After stirring at 80° C. for 16 h, the reaction mixture waspoured into sat. NaHCO₃(50 mL) and extracted using DCM (50 mL×3). Thecombined organic layer was washed with brine (50 mL), dried with sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography eluting with 70% ethyl acetate inhexane (700 mg). The compound was further purified by preparative HPLCmethod using (a) 0.1% formic acid in water and (b); 100% acetonitrile asmobile phase solvents to afford Intermediate-BB82 (200 mg, Yield: 15%),MS (ES): m/z 233.9.[M+H]⁺, LCMS purity 100%.

Synthesis of 7-(difluoromethyl)-3-iodoimidazo[1,2-a]pyridine(Intermediate BB84)

Step-1 Synthesis of 7-(difluoromethyl)-3-iodoimidazo[1,2-a]pyridine(Intermediate-BB84)

To a solution of 3-iodoimidazo[1,2-a]pyridine-7-carbaldehyde (2 g, 7.35mmol, 1 eq) in DCM (20 mL) at 0° C. was added diethylaminosulfurtrifluoride (3.5 g, 22.05 mmol, 3 eq). After warming to RT and stirringfor 45 min, the reaction mixture was quenched with saturated sodiumbicarbonate solution (100 mL) and extracted with ethyl acetate (100mL×3). The combined extract was dried over sodium sulfate andconcentrated under reduced pressure to afford7-(difluoromethyl)-3-iodoimidazo[1,2-a]pyridine (Intermediate-BB84) (0.6g, 27.76%) MS (ES): m/z 295.1 [M+H]⁺

Synthesis of8-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine(Intermediate BB87)

Step-1 Synthesis of8-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine(Intermediate BB87)

To a solution of 3-bromo-8-fluoroimidazo[1,2-a]pyridine (IntermediateBB87-1) (1.0 g 4.67 mmol, 1.0 eq.) and isopropyl boronic ester (4.3 g23.0 mmol, Seq.) in THF (10.0 mL) was added isopropyl MgCl.LiCl (TurboGrignard) (10.1 mL, 2.2 eq.) at RT. After stirring at RT for 20 min, thereaction mixture of Intermediate BB87 was use as such without aqueousworkup and purification. MS (ES): m/z 263.4 (M+H)⁺.

Synthesis of 8-bromoimidazo[1,2-c]pyrimidine (Intermediate BB88)

Step-1. Synthesis of 8-bromoimidazo[1,2-c]pyrimidine (Intermediate BB88)

To a solution of Intermediate BB88-1 (0.350 g, 2 mmol) in acetonitrile(5 mL) were added KHSO₄ (685 mg, 5.02 mmol, 2.5 eq) and bromoacetaldehyde diethyl acetal (0.4 g, 5.02 mmol, 2.5 eq). After stirringat 100° C. for 16 h, the reaction mixture was poured into water andextracted using 10% MeOH/DCM. The organic layer was washed with brinesolution, dried over sodium sulfate, and concentrated under reducedpressure (0.3.5 g). The residue was purified by silica getchromatography eluting with 2.5% MeOH in DCM to afford Intermediate-BB88(0.180 g, 7.1%). MS (ES): m/z 199.5 (M+H)⁺.

Synthesis of 7-(difluoromethyl)-8-fluoro-3-iodoimidazo[1,2-a]pyridine(Intermediate BB89)

Step-1 Synthesis of (8-fluoroimidazo[1,2-a]pyridin-7-yl)methanol(Intermediate-BB89-2)

To a solution of methyl 8-fluoroimidazo[1,2-a]pyridine-7-carboxylate (5g, 25.75 mmol, 1 eq) in THF (50 mL) at 0° C. was added LAH (1.7 g, 51.4mmol, 2 eq). After warming to RT and stirring for 90 min, the reactionmixture was poured into sodium sulfate decahydrate and diluted withethyl acetate (100 mL). The organic layer was filtered and concentratedunder reduced pressure to afford Intermediate-BB89-2 (4 g, 93%) MS (ES):m/z 167.1 [M+H]⁺

Step-2 Synthesis of 8-fluoroimidazo[1,2-a]pyridine-7-carbaldehyde(Intermediate-BB89-3)

To a solution of Intermediate-BB89-2 (4 g, 24.07 mmol, 1 eq) in DCM (20mL) at 0° C. was added Dess Martin periodinane (30 g, 72.21 mmol, 3 eq)portion wise. After warming to RT and stirring for 45 min, the reactionmixture was quenched with saturated sodium bicarbonate solution (250 mL)and extracted with ethyl acetate (100 mL×3). The combined extract wasdried over sodium sulfate and concentrated under reduced pressure toafford Intermediate-BB89-3 (3.2 g, 80%) MS (ES): m/z 165.2 [M+H]⁺

Step-3 Synthesis of 8-fluoro-3-iodoimidazo[1,2-a]pyridine-7-carbaldehyde(Intermediate-BB89-4)

8-fluoro-3-iodoimidazo[1,2-a]pyridine-7-carbaldehyde(Intermediate-BB89-4) were carried out following representativeprocedures described in step-1 of Intermediate-BB81 (1.5 g, 60.6%) MS(ES): m/z 313.6 [M+H]⁺

Step-4 Synthesis of7-(difluoromethyl)-8-fluoro-3-iodoimidazo[1,2-a]pyridine(Intermediate-BB89)

7-(difluoromethyl)-8-fluoro-3-iodoimidazo[1,2-a]pyridine(Intermediate-BB89) were carried out following representative proceduresdescribed in Intermediate-BB84 (0.5 g, 30.98%) MS (ES): m/z 313.6 [M+H]⁺

Synthesis of 3-bromo-7-methylpyrazolo[1,5-a]pyridine (Intermediate BB90)

Step-1 Synthesis of 3-bromo-7-methylpyrazolo[1,5-a]pyridine(Intermediate BB90)

To a solution of Intermediate BB90-1 (0.500 g, 2.8 mmol) in DMF (15 mL)were added NaHCO₃(715 mg, 8.51 mmol, 3 eq) and NBS (0.498 g, 2.8 mmol, 1eq). After stirring at RT for 30 min, the reaction mixture was pouredinto water and extracted with EtOAc (20 mL×3). The combined organiclayer was washed with brine solution, dried over sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicaget chromatography eluting with 5% EtOAc in hexane to affordIntermediate BB90 (0.470 g, 74.5%). MS (ES): m/z 211.3 (M+H)⁺.

Synthesis of 3-bromo-6-methylpyrazolo[1,5-a]pyridine (Intermediate BB91)

Intermediate BB91 was synthesize using same identical method asIntermediate-BB90 starting with Intermediate BB91-1

Synthesis of pyrrolo[1,2-b]pyridazin-4-yl 4-methylbenzenesulfonate(Intermediate BB92)

Step-1 Synthesis of pyrrolo[1,2-b]pyridazin-4-yl4-methylbenzenesulfonate (Intermediate BB92)

To a solution of Intermediate-BB92-1(0.600 g, 4.46 mmol) in DCM (10 mL)at 0° C. with TEA (1.9 mL, 13.43 mmol, 3 eq) was added 4-toluenesulfonylchloride (1.56 g, 5.35 mmol, 1.2 eq). After stirring at RT for 1.5 h,the reaction mixture was poured into water and extracted with EtOAc (30mL×3). The organic layer was washed with brine solution, dried oversodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica get chromatography eluting with 8% EtOAc in hexane toafford Intermediate-BB92 (0.6 g, 46.5%). MS (ES): m/z 289.6 (M+H)⁺.

The following intermediates were available commercially or prepared byknown literature routes.

TABLE 5 Commercially available intermediates or intermediates preparedby known literature routes. # Structure BB9

BB10

BB17

BB39

BB40

BB41

BB42

BB45

BB46

BB47

BB48

BB49

BB51

BB52

BB53

BB54

BB57

BB58

BB59

BB60

BB61

BB64

BB65

BB66

BB67

BB73

BB74

BB79

BB83

BB85

BB86

BB16

Synthesis of tert-butyl 3-bromo-2-ethyl-1H-indole-1-carboxylate(Intermediate BC1)—Method A2

Step 1: 3-Bromo-2-ethyl-1H-indole (Intermediate BC1-2)

N-Bromosuccinimide (613 mg, 3.44 mmol) was added portion wise to asolution of 2-ethyl-1H-indole (500 mg, 4.33 mmol) in DMF (10 mL). Afterstirring at RT for 16 h, the reaction was quenched with a saturatedNaHCO₃ solution and extracted into EtOAc (3×). The combined extractswere washed with brine, dried over MgSO4, and concentrated in vacuo toafford the title compound (Intermediate BC1-2) (927 mg, quant) as apurple oil. ¹H NMR (400 MHz, CDCl₃): δ 8.03 (s, 1H), 7.51-7.46 (m, 1H),7.31-7.26 (m, 1H), 7.15 (t, J=3.7 Hz, 2H), 2.82 (q, J=7.7 Hz, 2H), 1.30(t, J=7.8 Hz, 3H).

Step 2: tert-Butyl 3-bromo-2-ethyl-1H-indole-1-carboxylate (BC1)

A solution of 3-bromo-2-ethyl-1H-indole (Intermediate BC1-2) (772 mg,3.44 mmol) in DCM (20 mL) was treated with triethylamine (0.53 mL, 3.79mmol), 4-(dimethylamino)pyridine (63 mg, 0.517 mmol) and di-tert-butylcarbonate (902 mg, 4.13 mmol). After stirring at RT for 16 h, thereaction was quenched with a saturated NaHCO₃ solution. The organicphase was washed with brine, dried by phase separator, and concentratedin vacuo to afford the title compound (Intermediate BC1) (1.14 g, quant)as a purple oil. ¹H NMR (400 MHz, CDCl₃): δ 8.10 (d, J=7.3 Hz, 1H), 7.47(d, J=7.7 Hz, 1H), 7.31-7.26 (m, 2H), 3.14 (q, J=7.2 Hz, 2H), 1.69 (s,9H), 1.24 (t, J=7.7 Hz, 3H).

Synthesis of tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate BC2)—Method B2

Step 1: tert-Butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate BC2)

To a degassed solution of tert-butyl3-bromo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (Intermediate BC2-1)(300 mg, 1.01 mmol) in 1,4-dioxane (6 mL) were added KOAc (297 mg, 3.03mmol) and bis(pinacolato)diboron (282 mg, 1.11 mmol). The solution waspurged with a N2 stream for 30 min before Pd(dppf)Cl₂ (37 mg, 0.051mmol) was added. After stirring in a sealed tube at 125° C. overnight,the reaction mixture was cooled to RT and diluted ethyl acetate (25 mL)and water (20 mL). The organic phase was separated, and the aqueousphase extracted with ethyl acetate (2×25 mL). The combined organicphases were washed with brine (10 mL), passed through a hydrophobic fritand concentrated in vacuo. The crude compound (BC2) was taken forwardsto the next step without further purification.

Synthesis of1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(Intermediate BC3)—Method C2

Step 1:1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(Intermediate BC2)

A solution of4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(Intermediate BC3-1) (200 mg, 0.819 mmol) in DMF (2 mL) at 0° C. wastreated with sodium hydride (60% dispersion in mineral oil, 72 mg, 1.64mmol). After 30 min at 0° C., 1-bromo-2-methoxy-ethane (228 mg, 1.64mmol) was added. After the reaction was compete, the mixture was pouredonto ice/water and extracted into EtOAc (5×). The organic phase wasdried by phase separator and concentrated in vacuo to provide the titlecompound (Intermediate BC3) as a crude residue which was used as is.

Synthesis of7-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine(Intermediate BC4)—Method D2

Step 1:7-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine(Intermediate BC4)

A solution of 3-bromo-7-methyl-imidazo[1,2-a]pyridine (IntermediateBC4-1) (530 mg, 2.51 mmol) and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (748 mg, 4.02 mmol)in anhydrous THF (7 mL) at −15° C. under a nitrogen atmosphere wastreated dropwise with isopropylmagnesium chloride lithium chloridecomplex solution (1.3 M in THF, 2.5 mL, 3.26 mmol). After stirring at−15° C. for 1.5 h, the reaction was quenched with a saturated NH₄C1solution and extracted into EtOAc (2×). The combined extracts werewashed with brine, dried over Na₂SO₄, and concentrated in vacuo to leavethe title compound (BC4) (731 mg, quant.) as an off-white solid whichwas used as is.

Synthesis of 3-iodo-7,8-dimethylimidazo[1,2-a]pyridine (IntermediateBC5)—Method E2

Step 1: 7,8-Dimethylimidazo[1,2-a]pyridine (Intermediate BC5-2)

3,4-Dimethylpyridin-2-amine (500 mg, 4.09 mmol) was dissolved in ethanol(10 mL) was treated with chloroacetaldehyde (50% in water, 1.0 mL, 8.19mmol). After stirring at 100° C. in a sealed tube for 18 h, the solventwas removed in vacuo and the residue purified by column chromatography(0-10% gradient elution with 7N methanolic ammonia in DCM) to afford thetitle compound (Intermediate BC5-2) (487 mg, 81%) as a yellow solid. ¹HNMR (400 MHz, DMSO): δ 8.33 (d, J=7.1 Hz, 1H), 7.87 (d, J=1.0 Hz, 1H),7.50 (d, J=1.0 Hz, 1H), 6.75 (d, J=6.8 Hz, 1H), 2.48 (s, 3H), 2.33 (s,3H).

Step 2: 3-Iodo-7,8-dimethylimidazo[1,2-a]pyridine (BC5)

A solution of 7,8-dimethylimidazo[1,2-a]pyridine (Intermediate BC5-2)(486 mg, 3.65 mmol) in chloroform (10 mL) was treated withN-iodosuccinimide (936 mg, 4.16 mmol). After stirring at RT for 18 h,the solvent was removed in vacuo and the residue purified by columnchromatography (0-100% gradient elution EtOAc in cyclohexane) to affordthe title compound (Intermediate BC5) (178 mg, 19%) as an off-whitesolid. ¹H NMR (400 MHz, CDCl3): δ 8.30 (d, J=2.0 Hz, 1H), 7.77 (s, 1H),7.67 (d, J=0.8 Hz, 1H), 2.68 (s, 3H), 2.40 (s, 3H).

Synthesis ofN-cyclopropyl-3-iodo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-6-carboxamide(Intermediate BC6)— Method F2

Step 1:N-cyclopropyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-6-carboxamide(Intermediate BC6-2)

A suspension of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-6-carboxylicacid (Intermediate BC6-1) (410 mg, 2.47 mmol) in DCM (10 mL) was treateddropwise with oxalyl chloride (0.25 mL, 2.96 mmol). After stirring at RTfor 30 min until homogeneous, the solvent was removed in vacuo. Theresidue was re-suspended in DCM (10 mL) at 0° C. and treated withtriethylamine (1.2 mL, 8.61 mmol) followed by cyclopropylamine (0.21 mL,2.96 mmol). After warming to RT and stirring for 16 h, the reaction wasquenched with water. The organic phase washed with a saturated NaHCO₃solution, dried by phase separator, and concentrated in vacuo to affordthe title compound (Intermediate BC6-2) (286 mg, 57%) as a grey solid.¹H NMR (400 MHz, DMSO): δ 7.96 (d, J=3.2 Hz, 1H), 7.18 (d, J=1.8 Hz,1H), 5.81 (t, J=0.8 Hz, 1H), 4.03 (dd, J=5.2, 12.7 Hz, 1H), 3.83 (dd,J=10.1, 12.6 Hz, 1H), 2.72-2.65 (m, 2H), 2.51-2.47 (m, 2H), 1.90-1.81(m, 1H), 1.67-1.55 (m, 1H), 0.49-0.44 (m, 2H), 0.28-0.23 (m, 2H).

Step 2:N-cyclopropyl-3-iodo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-6-carboxamide(BC6)

Step 2 was carried out following the representative procedure describedin Intermediate BC5—Method E2, Step 2 using DMF as solvent. The crudeproduct was used directly in subsequent reactions.

Synthesis ofN-cyclopropyl-3-iodo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxamide(Intermediate BC7)—Method G2

Step 1: N-Ethylimidazo[1,2-a]pyridine-7-carboxamide (Intermediate BC7-2)

A suspension of imidazo[1,2-a]pyridine-7-carboxylic acid hydrochloride(Intermediate BC7-1) (500 mg, 2.52 mmol) in acetonitrile (5.0 mL) andTHF (1.5 mL) was treated with ethylamine (2M in THF, 1.5 mL, 3.02 mmol),1-methylimidazole (723 mg, 8.81 mmol) followed bychloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (848 mg,3.02 mmol). After stirring at RT for 18 h, the solvent was removed invacuo and the residue purified by column chromatography (0-10% methanolgradient in DCM). Trituration with acetonitrile afforded the titlecompound (Intermediate BC7-2) (132 mg, 28%) as an off-white solid. ¹HNMR (400 MHz, DMSO): δ 8.69 (t, J=5.4 Hz, 1H), 8.65 (dd, J=0.9, 7.0 Hz,1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.76 (d, J=0.9 Hz, 1H), 7.36 (dd,J=1.9, 7.4 Hz, 1H), 3.35 (m, 2H), 1.20 (t, J=7.2 Hz, 3H).

Step 2:N-Cyclopropyl-3-iodo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxamide(BC7)

Step 2 was carried out following the representative procedure describedin Intermediate BC5—Method E2, Step 2 to afford the title compound(Intermediate BC7) (220 mg, 88%) as a light brown solid. ¹H NMR (400MHz, DMSO): δ 8.77 (t, J=5.5 Hz, 1H), 8.44 (dd, J=0.8, 7.1 Hz, 1H), 8.20(dd, J=0.9, 1.6 Hz, 1H), 7.90 (s, 1H), 7.53 (dd, J=1.8, 7.4 Hz, 1H),3.35 (m, 2H), 1.21 (t, J=7.3 Hz, 3H).

Synthesis of 3-iodo-N-(2-methoxyethyl)imidazo[1,2-a]pyridin-7-amine(Intermediate BC8)—Method H2

Step 1: N-(2-methoxyethyl)imidazo[1,2-a]pyridin-7-amine (IntermediateBC8-2)

A mixture of 7-bromoimidazo[1,2-a]pyridine (Intermediate BC8-1) (800 mg,4.06 mmol), 2-methoxyethylamine (335 mg, 4.47 mmol), t-BuXPhos (122 mg,0.812 mmol), Pd₂(dba)₃ (372 mg, 0.406 mmol) and sodium tert-butoxide(975 mg, 10.15 mmol) in toluene (40 mL) was degassed, purged withnitrogen and heated at 110° C. for 18 h. The solvent was removed invacuo and the residue purified by column chromatography (0-10% methanolgradient in DCM) to afford the title compound (Intermediate BC8-2) (407mg, 52%) as a brown oil which was used directly in subsequent reactions.

Step 2: 3-iodo-N-(2-methoxyethyl)imidazo[1,2-a]pyridin-7-amine (BC8)

Step 2 was carried out following the representative procedure describedin Intermediate BC5—Method E2, Step 2 to afford the title compound(Intermediate BC8) (610 mg, 92%) as a light brown residue which was usedcrude in subsequent reactions.

Synthesis of 7-fluoro-3-(tributylstannyl)imidazo[1,2-a]pyridine(Intermediate BC9)—Method 12

A solution of 3-bromo-7-fluoroimidazo[1,2-a]pyridine (IntermediateBC9-1) (400 mg, 1.86 mmol) in anhydrous THF (15 mL) at −15° C. under anitrogen atmosphere was treated dropwise with isopropylmagnesiumchloride lithium chloride complex solution (1.3 M in THF, 1.5 mL, 2.05mmol). After stirring for 15 min, tributyltin chloride (0.53 mL, 1.95mmol) was added. After warming to RT and stirring for 1 h, the reactionwas quenched with a saturated NH₄C1 solution and extracted into EtOAc(2×). The combined extracts were dried over MgSO4 and concentrated invacuo to afford the title compound (Intermediate BC9) (617 mg, 78%) as ayellow oil which was used crude in subsequent reactions.

The following BC intermediates were prepared according to any ofIntermediate Methods A2-I2 as described above.

TABLE 6 BC intermediates prepared according to any of IntermediateMethods A2-I2. # STRUCTURE Method BC22

Method A2 (Step 2) and Intermediate BC1 - Method A2 (Step 1) startingwith 3- bromo-2-methyl- 1H-pyrrolo[2,3-b] pyridine BC29

Method A2, Step 2 starting from 3- bromo-6-methyl- 5-azaindole BC37

Method C2 using isopropyl iodide BC38

Method C2 using bromoethane BC44

Method B2 using 4-bromo-1- methyl-1H- pyrazolo[3,4- b]pyridine BC48

Method C2 followed by Intermediate BC2 - Method B2 using 4-bromo-5-fluoro- 1H-pyrrolo[2,3- b]pyridine and iodomethane BC53

Method A2, Step 2 using 4-bromo-6- methyl-1H- pyrrolo[2,3- b]pyridineBC54

Method A2, Step 2 using 4-bromo-5- methyl-1H- pyrrolo[2,3- b]pyridineBC55

Method D2 using 3-bromo-5,6,7,8- tetrahydroimidazo [1,2-a]pyridine BC57

Method C2 using 4-bromo-7H- pyrrolo[2,3- d]pyrimidine and iodomethaneBC65

Method C2 using 4-bromo-5- methyl-1H- pyrrolo[2,3- b]pyridine andiodomethane BC67

Method C2 using 4-bromo-6- methyl-1H- pyrrolo[2,3- b]pyridine andiodomethane BC68

Method C2 using 8-bromo-3,4- dihydro-2H- pyrido[3,2- b][1,4]oxazine andiodomethane BC73

Method D using 7-bromo-1- methyl-1H- imidazo[4,5- b]pyridine BC74

Method C2 using 5-bromo-1,2,3,4- tetrahydro-1,8- naphthyridine andiodomethane BC75

Method C2 using 4-bromo-7-aza- indole and sodium bromo-difluoro- acetateBC87

Method E2 using 3-methyl-pyrazin- 2-amine BC91

Method D2 using 7-fluoro-3- iodoimidazo[1,2- a]pyridine BC97

Method E2 starting with 5- methyl-pyridazin- 3-amine BC98

Method E2 using 2-amino-3- fluoroiso- nicotinonitrile BC100

Method D2 using 7-cyano-3- iodoimidazo[1,2- a]pyridine BC102

Method I2 using 3-bromo- imidazo[1,2-b] pyridazine BC103

Method B2 using BC75 BC104

Method I2 using 3-bromo- imidazo[1,2-a] pyrazine BC105

Method E2 using 3-fluoro-4- methylpyridin-2- amine BC107

Method B2 using 8-bromo-3- methylimidazo [1,2-a]pyridine BC110

Method B2 using 4-bromo-1,2- dimethyl-1H- pyrrolo[2,3- b]pyridine BC111

Method I2 using 3-bromo- imidazo[1,2-a] pyridine BC112

Method I2 using 3-bromo-2- methylimidazo [1,2-a]pyridine BC113

Method I2 using 3-bromo-8- methylimidazo [1,2-a]pyridine BC114

Method I2 using 3-bromo-8- fluoroimidazo [1,2-a]pyridine BC115

Method E2, Step 2 using 2- (imidazo[1,2- a]pyridin-7- yloxy)-N,N-dimethylethan-1- amine BC116

Method E2 using 4-fluoro-3- methoxypyridin- 2-amine BC117

Method E2 using 4-fluoro-3- methylpyridin-2- amine BC118

Method D2 using 3-bromo-8- fluoroimidazo [1,2-a]pyridine BC119

Method E2 using 3- (difluoromethyl) pyridin-2-amine BC120

Method I2 using 8- (difluoromethyl)- 3- iodoimidazo[1,2- a]pyridineBC123

Method I2 using BC117 BC124

Method D2 using 8-methoxy-3- iodoimidazo[1,2- a]pyridine BC125

Method A2 using 2-Phenyl-1H- indole BC126

Method I2 using 3- bromoimidazo [1,2-a]pyrimidine BC127

Method D2 using 8-chloro-3- iodoimidazo[1,2- a]pyridine

The following intermediates were available commercially or prepared byknown literature routes.

TABLE 7 Intermediates available commercially or prepared by knownliterature routes. # Structure BC10

BC11

BC12

BC13

BC14

BC15

BC16

BC17

BC18

BC19

BC20

BC21

BC23

BC24

BC25

BC26

BC27

BC28

BC30

BC31

BC32

BC33

BC34

BC35

BC36

BC39

BC40

BC41

BC42

BC43

BC45

BC46

BC47

BC49

BC50

BC51

BC52

BC56

BC58

BC59

BC60

BC61

BC62

BC63

BC64

BC66

BC69

BC70

BC71

BC72

BC76

BC77

BC78

BC79

BC80

BC81

BC82

BC83

BC84

BC85

BC86

BC88

BC89

BC90

BC92

BC93

BC94

BC95

BC96

BC99

BC101

BC106

BC108

BC109

BC121

BC122

Example 1. Method A Synthesis of7-((5-(4-Methylpiperazin-1-yl)pyridin-2-yl)amino)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-6)

Step 1. 5-Bromo-2-chloro-N-methoxy-N-methylnicotinamide (1.2)

A mixture of 5-bromo-2-chloronicotinic acid (1.1) (4.00 g, 16.92 mmol)in thionyl chloride (20 mL) was heated at 80° C. for 2 h. Concentratedin vacuo and azeotroped with toluene (2×10 mL). The residue was taken upin DCM and cooled to 0° C. The mixture was treated with N,O-dimethylhydroxylamine hydrochloride (2.06 g, 21.15 mmol) followed bytrimethylamine (7.1 mL, 50.75 mmol) and stirred for 1 h. The mixture wasdiluted with DCM, washed with 10% citric acid solution, saturatedaqueous NaHCO₃ solution, water and brine, dried over Na₂SO₄, andconcentrated in vacuo to leave the title compound (1.2) (3.81 g, 81%) asa pale orange solid. m/z=280.9 [M+H]⁺, ¹H NMR (400 MHz, CDCl₃): δ 8.50(d, J=2.0 Hz, 1H), 7.83-7.78 (m, 1H), 3.53 (s, 3H), 3.39 (s, 3H).

Step 2. 5-Bromo-2-chloronicotinaldehyde (1.3)

A solution of 5-bromo-2-chloro-N-methoxy-N-methylnicotinamide (1.2)(3.80 g, 13.59 mmol) in dry THF (30 mL) at −10° C. under a nitrogenatmosphere was treated dropwise with LiAlH₄ (1M solution in THF, 5.4 mL,5.44 mmol). After the addition, the mixture was allowed to warm to RTand stirred for 18 h. The reaction was cooled to back down to 0° C.,quenched with careful addition of 1M KHSO₄ solution, and extracted intoEtOAc (3×20 mL). The combined extracts were washed with brine, driedover Na₂SO₄, and concentrated in vacuo. The residue was purified bysilica gel chromatography (0-25% gradient elution EtOAc in iso-hexane)to leave the title compound (1.3) (2.31 g, 77%) as a white solid.m/z=220.9 [M+H]⁺, ¹H NMR (400 MHz, CDCl₃): δ 10.37 (s, 1H), 8.66 (d,J=2.6 Hz, 1H), 8.33 (d, J=2.6 Hz, 1H).

Step 3. 5-Bromo-2-chloro-3-(dimethoxymethyl)pyridine (1.4)

A solution of 5-bromo-2-chloronicotinaldehyde (1.3) (18.66 g, 84.6 mmol)in MeOH (50 mL) was treated with p-toluenesulfonic acid (1.61 g, 0.85mmol), followed by trimethyl orthoformate (37 mL, 338.4 mmol). Theresulting mixture was heated to reflux for 2 h. The solvent was thenremoved in vacuo and the residue was taken up in EtOAc (100 mL) andwashed with saturated aqueous NaHCO₃(2×100 mL), water (100 mL) and brine(100 mL), dried with MgSO₄, filtered and the solvent removed in vacuo toyield the title compound (1.4) (16 g, 70%) as a clear oil. m/z=267.5[M+H]⁺, ¹H NMR (400 MHz, CDCl₃) δ 8.42 (d, 1H), 8.08 (d, 1H), 5.53 (s,1H), 3.41 (s, 6H).

Step 4. Ethyl 5-bromo-2-chloro-3-(dimethoxymethyl)isonicotinate (1.5)

A degassed solution of LDA (2 M in THF/Heptane/Ethylbenzene, 5.16 mL,10.32 mmol) in dry THF (25 mL) was cooled down to −78° C. before asolution of 5-bromo-2-chloro-3-(dimethoxymethyl)pyridine (1.4) (2.5 g,9.38 mmol) in dry and degassed THF (10 mL) was added dropwise. After 30min, ethyl chloroformate (2.68 mL, 28.14 mmol) was added dropwise andthe reaction stirred at −50° C. for 40 min. The reaction was quenchedwith saturated aqueous NaHCO₃ (25 mL) and allowed to warm to RT. Themixture was extracted with ethyl acetate (2×25 mL) and the combinedorganic phases were washed with brine (20 mL), dried with MgSO4,filtered, and then concentrated in vacuo. The residue was purified bycolumn chromatography (0-50% gradient elution EtOAc in iso-hexane) toafford the title compound (1.5) (2.01 g, 63%) as a yellow oil. m/z=339.7[M+H]⁺, ¹H NMR (400 MHz, CDCl₃) δ 8.52 (s, 1H), 5.53 (s, 1H), 4.43 (q,2H), 3.41 (s, 6H), 1.41 (t, 3H)

Step 5. Ethyl 5-bromo-2-chloro-3-formylisonicotinate (1.6)

A solution of ethyl 5-bromo-2-chloro-3-(dimethoxymethyl)isonicotinate(5) (6.9 g, 20.4 mmol) in MeCN (200 mL) and H₂O (4 mL) was treated withlithium tetrafluoroborate (1M in MeCN, 20.4 mL, 20.4 mmol) and stirredat 90° C. for 16 h. After that time, volatiles were eliminated, theresidue taken up in DCM and washed with H₂O (2×30 mL). Solvent wasremoved in vacuo to afford the title compound (1.6) (5.8 g, 97%) as anorange oil. m/z=293.6 [M+H]⁺, ¹H NMR (400 MHz, CDCl₃) δ 10.35 (s, 1H),8.73 (s, 1H), 4.53 (q, 2H), 3.41 (s, 6H), 1.44 (t, 3H).

Step 6.7-Bromo-4-chloro-2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(1.7)

A solution of ethyl 5-bromo-2-chloro-3-(dimethoxymethyl)isonicotinate(1.6) (5.8 g, 19.83 mmol) in DCM (40 mL) was treated with acetic acid(3.4 mL, 59.48 mmol) and stirred at RT for a few min before2,4-dimethoxybenzylamine (3.28 mL, 21.81 mmol) was added dropwise. After3 h sodium cyanoborohydride (1.87 g, 29.74 mmol) was added portion wiseand the reaction stirred at RT. The mixture was then filtered through apad of Celite, the solvent was removed in vacuo and the residue waspurified by column chromatography (0-60% gradient elution EtOAc iniso-hexane) to afford the desired compound (1.7) (3.5 g, 44%) as ayellow oil. m/z=366.5 [M+H]⁺, ¹H NMR (400 MHz, CDCl₃) δ 8.53 (s, 1H),7.28 (d, J=7.7 Hz, 1H), 6.49-6.42 (m, 2H), 4.75 (s, 2H), 4.28 (s, 2H),3.86 (s, 3H), 3.80 (s, 3H).

Step 7.4-Chloro-2-(2,4-dimethoxybenzyl)-7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrrolo[1,4-c]pyridin-1-one(1.8)

To a solution of7-bromo-4-chloro-2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(1.7) (2 g, 5.03 mmol) in dry 1,4-dioxane (60 mL) was added Cs₂CO₃ (3.27g, 10.06 mmol) followed by 5-(4-methylpiperazin-1-yl)pyridin-2-amine(AA2) (preparation described in WO2015131080, 1.06 g, 5.54 mmol). Themixture was purged with a N2 stream for 10 min before Xantphos (350 mg,0.604 mmol) and Pd₂(dba)₃ (461 mg, 0.503 mmol) were added. The mixturewas degassed for 10 more min. The reaction was then stirred at 120° C.for 2 h. After cooling to RT, the reaction mixture was poured intosaturated aqueous NH₄C1 solution (30 mL) and filtered through a CelitePad. The mixture was extracted with ethyl acetate (2×25 mL). Thecombined organic phases were washed with brine (25 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The crudeproduct was purified by column chromatography (0-100% gradient elutionEtOAc in iso-hexane) to afford the desired compound (1.8) (1.6 g, 62%)as a dark orange solid. m/z=478.1 [M+H]⁺, ¹H NMR (400 MHz, DMSO): δ9.41-9.38 (m, 1H), 8.53 (d, J=9.1 Hz, 1H), 8.05-8.02 (m, 1H), 7.52-7.46(m, 1H), 7.08 (d, J=8.8 Hz, 1H), 4.75 (s, 2H), 3.19-3.13 (m, 4H),2.53-2.47 (m, 4H), 2.28 (s, 3H), 1.59 (s, 9H).

Step 8. tert-Butyl3-(2-(2,4-dimethoxybenzyl)-7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(1.9)

A mixture of4-chloro-2-(2,4-dimethoxybenzyl)-7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(1.8) (250 mg, 0.491 mmol), 1-BOC-7-azaindole-3-boronic acid pinacolester (203 mg, 0.589 mmol), Pd(dppf)Cl₂ 1:1 DCM complex (20 mg, 5 mol %)and Cs₂CO₃ (2M solution, 614 μL, 1.23 mmol) in 1,4-dioxane (5 mL) wasdegassed, purged with nitrogen and heated at 100° C. for 6 h. Thereaction mixture was diluted with EtOAc (20 mL), washed with water (15mL) and brine (15 mL), dried over Na₂SO₄, and concentrated in vacuo. Theresidue was purified by silica gel chromatography (0-10% gradientelution MeOH in DCM) to leave the title compound (1.9) (290 mg, 85%) asan orange residue which was used directly in next step.

Step 9.7-45-(4-Methylpiperazin-1-yl)pyridin-2-yl)amino)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-6)

A 5 mL microwave vial was charged with tert-butyl3-(2-(2,4-dimethoxybenzyl)-745-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(1.9) (289 mg, 0.418 mmol) and TFA (5 mL) and heated at 160° C. for 10mins in a Biotage Initiator® microwave. The mixture was concentratedunder vacuum and triturated with NH₄OH. The precipitate was collected byfiltration, washed with water and air dried. The crude product waspurified by preparative HPLC to afford the title compound (I-6) (92 mg,50%) as an orange solid. m/z=441.2 [M+H]⁺, ¹H NMR (400 MHz, DMSO): δ12.11-12.06 (m, 1H), 9.87 (s, 1H), 9.34 (s, 1H), 9.21 (s, 1H), 8.94 (d,J=7.1 Hz, 1H), 8.35 (d, J=3.0 Hz, 1H), 8.08 (d, J=2.8 Hz, 1H), 7.89 (d,J=2.3 Hz, 1H), 7.50 (dd, J=2.8, 8.8 Hz, 1H), 7.23 (dd, J=4.5, 7.8 Hz,1H), 7.05 (d, J=8.8 Hz, 1H), 4.78 (s, 2H), 3.21 (dd, J=6.4, 6.4 Hz, 4H),2.70-2.63 (m, 4H), 2.38 (s, 3H).

Example 2. Method C Synthesis of4-(Imidazo[1,2-a]pyridin-3-yl)-7-45-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-56)

Step 1. 2-Bromo-5-chloronicotinaldehyde (2.2)

A solution of 2,3-dibromo-5-chloropyridine (2.1) (25.29 g, 93.21 mmol)in THF (200 mL) at −40° C. under a nitrogen atmosphere was treateddropwise with isopropyl magnesium chloride (2M in THF, 50.8 mL, 101.59mmol) and stirred for 1 h. DMF (21.1 mL, 272.20 mmol) was added dropwiseand the mixture allowed to warm to RT over 30 min. The reaction wasquenched with 1M HCl and extracted into tert-butyl methyl ether (3×).The combined extracts were washed with saturated aqueous NaHCO₃solution, water, and brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo to afford the title compound (2.2) (20.35 g, 99%)as a beige solid. m/z=221.2 [M+H]⁺, ¹H NMR (400 MHz, CDCl₃): δ 10.29 (s,1H), 8.54 (d, J=2.8 Hz, 1H), 8.13 (d, J=2.8 Hz, 1H).

Step 2. 2-Bromo-5-chloronicotinaldehyde (2.3)

A mixture of 2-bromo-5-chloronicotinaldehyde (2.2) (25.40 g, 115.22mmol), triethyl orthoformate (37.8 mL, 345.66 mmol) and p-toluenesulfonic acid monohydrate (2.19 g, 11.52 mmol) in methanol (300 mL) washeated at reflux for 18 h. The cooled mixture was concentrated in vacuoand passed through a silica pad eluting with 20% EtOAc in iso-hexane toleave the title compound (2.3) (28.61 g, 93%) as a yellow oil. m/z=267.2[M+H]⁺, ¹H NMR (400 MHz, CDCl₃): δ 8.32 (d, J=2.5 Hz, 1H), 7.89 (d,J=2.5 Hz, 1H), 5.47 (s, 1H), 3.41 (s, 6H).

Step 3. Ethyl 2-bromo-5-chloro-3-(dimethoxymethyl)isonicotinate (2.4)

A solution of LDA (2M in THF/heptane/ethylbenzene, 69.8 mL, 139.5 mmol)in dry THF (130 mL) at −50° C. under a nitrogen atmosphere was treateddropwise with a solution of 2-bromo-5-chloro-3-(dimethoxymethyl)pyridine(2.3) (28.60 g, 107.31 mmol) in dry THF (70 mL) over 40 min. After theaddition, the mixture was stirred for an additional 40 min. Ethylchloroformate (30.7 mL, 321.93 mmol) was added dropwise and stirringcontinued at −50° C. for 40 min. The reaction was quenched withsaturated aqueous NaHCO₃ solution and extracted into EtOAc (3×). Thecombined extracts were washed with brine, dried over Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified by silica gelchromatography (0-30% gradient elution EtOAc in iso-hexane) to affordthe title compound (2.4) (26.51 g, 73%) as a pale yellow oil. m/z=339.6[M+H]⁺, ¹H NMR (400 MHz, CDCl₃): δ 8.38 (s, 1H), 5.50-5.49 (m, 1H), 4.42(q, J=7.2 Hz, 2H), 3.43-3.42 (m, 6H), 1.40 (dd, J=7.2, 7.2 Hz, 3H).

Step 4. Ethyl 2-bromo-5-chloro-3-formylisonicotinate (2.5)

A mixture of ethyl 2-bromo-5-chloro-3-(dimethoxymethyl)isonicotinate(2.4) (26.50 g, 78.27 mmol) and lithium tetrafluoroborate (10.27 g,109.57 mmol) acetonitrile (250 mL) and water (15 mL) was heated at 75°C. for 18 h. The cooled mixture was concentrated in vacuo, taken up inEtOAc, washed with saturated aqueous NaHCO₃ solution, water, and brine,dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by silica gel chromatography (0-30% gradient elution EtOAc iniso-hexane) to afford the title compound (15) (13.94 g, 61%) as a yellowoil. m/z=293.5 [M+H]⁺, ¹H NMR (400 MHz, DMSO): δ 8.62 (s, 1H), 7.21 (d,J=8.3 Hz, 1H), 4.68 (s, 2H), 3.87 (s, 3H).

Step 5.4-Bromo-7-chloro-2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(2.6)

To a solution of ethyl 2-bromo-5-chloro-3-formylisonicotinate (2.5)(13.93 g, 47.62 mmol) and acetic acid (8.18 mL, 142.87 mmol) in DCM (200mL) was added MgSO4 followed by 2,4-dimethoxybenzylamine (7.87 mL, 52.38mmol) and the mixture stirred at RT for 18 h. Sodium borohydride (2.70g, 71.43 mmol) was added portion wise and the reaction was stirred for 2h. The mixture was diluted with DCM, washed with saturated aqueousNaHCO₃ solution, water, and brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography (0-50% gradient elution EtOAc in DCM). The yellow residueobtained was triturated with diethyl ether to leave the title compound(2.6) (7.12 g, 38%) as a white solid. m/z=398.6 [M+H]⁺, ¹H NMR (400 MHz,DMSO): δ 8.61 (s, 1H), 7.20 (d, J=8.3 Hz, 1H), 6.64 (d, J=2.3 Hz, 1H),6.54 (dd, J=2.1, 8.2 Hz, 1H), 4.67 (s, 2H), 4.36 (s, 2H), 3.87 (s, 3H),3.81 (s, 3H).

Step 6:7-chloro-2-(2,4-dimethoxybenzyl)-4-(imidazo[1,2-a]pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(2.7)

A mixture of4-bromo-7-chloro-2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(2.6) (300 mg, 0.756 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine(369 mg, 7.57 mmol), Pd(dppf)Cl₂ 1:1 DCM complex (62 mg, 10 mol %) andCs₂CO₃ (2M solution, 950 μL, 1.89 mmol) in 1,4-dioxane (10 mL) wasdegassed, purged with nitrogen and heated at 100° C. for 4 h. Thereaction mixture was diluted with EtOAc, washed with water and brine,dried over Na₂SO₄, and concentrated in vacuo. The residue was purifiedby silica gel chromatography (0-100% gradient elution EtOAc in DCM) toleave the title compound (2.7) (168 mg, 51%) as a light brown solid.

Alternatively, Step 6 was carried out using the procedure describedbelow:

A mixture of4-bromo-7-chloro-2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(2.6) (500 mg, 1.26 mmol), 3-(tributylstannyl)imidazo[1,2-a]pyridine(399 mg, 1.64 mmol) and Pd(PPh₃)₄ (73 mg, 0.063 mmol) in 1,4-dioxane (10mL) was degassed, purged with nitrogen and heated at 90° C. for 4 h. Theprecipitate was collected from the cooled reaction mixture, washed withdiethyl ether, and dried to leave the title compound (2.7) (298 mg, 54%)as an off-white solid. ¹H NMR (400 MHz, DMSO): δ 9.79 (d, J=6.9 Hz, 1H),8.83 (s, 1H), 8.18-8.14 (m, 1H), 7.81-7.75 (m, 1H), 7.54-7.46 (m, 1H),7.19-7.13 (m, 2H), 6.61 (s, 1H), 6.53-6.48 (m, 1H), 4.77 (s, 2H), 4.69(s, 2H), 3.85 (s, 3H), 3.77 (s, 3H).

Step 7 and 8 were carried out following representative proceduresdescribed in Example 1, and characterization of 1-56 is provided inExample 21.

Example 3. Method D Synthesis of7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-4-(1H-pyrrolo[3,2-b]pyridin-3-yl)isoindolin-1-one(I-26)

Step-1 Synthesis of Methyl 3-chloro-2-methylbenzoate (3.0a)

To a mixture of 3-chloro-2-methylbenzoic acid (300 g 1.75 mol) andpotassium carbonate (606 g, 4.39 mol) in DMF (2500 mL) were addediodomethane (275 g, 1.93 mol). After stirring at RT for 16 h, thereaction was quenched with water and extracted with ethyl acetate. Thecombined extracts were washed with brine, dried over sodium sulfate, andconcentrated under vacuum to afford title compound as light brown liquid(3.0a) (320 g, yield: 98.16%). MS (ES): m/z 185.7 [M+1]⁺

Step-2 Synthesis of Methyl 2-(bromomethyl)-3-chlorobenzoate (3.0)

To a solution of methyl 3-chloro-2-methylbenzoate (3.0a) (320 g, 1.72mol) in carbon tetrachloride (3000 mL) were added N-bromosuccinimide(336.2 g, 1.88 mol) and benzoyl peroxide (0.798 g, 0.0032 mol) at RT.After stirring at 90° C. for 4 h, the reaction was poured into ice/water(˜5000 mL) water and extracted with ethyl acetate. The combined extractswere washed with brine, dried over sodium sulfate, and concentratedunder vacuum to afford title compound as light brown liquid (3.0) (400g, yield: 87.71%). MS (ES): m/z 263.5, 265.6 [M]⁺, [M+2]⁺

Step-3 Synthesis of 4-chloroisoindolin-1-one (3.1)

To a solution of methyl 2-(bromomethyl)-3-chlorobenzoate (3.0) (400 g,1.51 mol), in methanol (3000 mL) was bubbled NH₃ for 1 h at 0° C. Afterstirring at RT for 16 h, the reaction was concentrated under vacuum anddiluted with water. The resulting solid compound was filtered and driedunder vacuum to obtained title compound as of white solid (3.1) (200 g,78.74%). MS (ES): m/z 168.6 [M+1]⁺

Step-4 Synthesis of 4-Chloro-7-nitroisoindolin-1-one (3.2)

To a solution of 4-chloro-isoindolin-1-one (3.1) (200 g, 1.19 mol) inc.H₂SO₄ (1200 mL) at −10° C. was added dropwise with HNO₃ (69-72% aq)(120 mL). After stirring cold for 2 h then warming to ambienttemperature for 2 h, the reaction was poured onto ice water (4000 mL).The precipitate was collected by filtration, washed with water, anddried to afford a pale yellow solid (3.2) (245 g, 96.84%). m/z=213.5[M+H]⁺, ¹H NMR (400 MHz, DMSO): δ 9.17 (s, 1H), 7.98-7.90 (m, 2H),4.47-4.46 (m, 2H).

Step-5 Synthesis of 7-Amino-4-chloroisoindolin-1-one (3.3)

To a solution of 4-chloro-7-nitroisoindolin-1-one 2 (3.2) (245 g, 1.15mol) in EtOH (2500 mL) and water (500 mL) were added iron powder (322 g,5.75 mol) and ammonium chloride (372.67 g, 6.90 mol). After mechanicallystirring at reflux for 2 h, the mixture was filtered through Celitewashing the filter cake with EtOAc and DCM (˜5 L). The filtrate wasconcentrated under vacuum to low volume whereby a solid precipitatedfrom solution. The precipitate was collected by filtration, washed withwater, and dried under vacuum to afford the title compound as a brownsolid (3.3) (200 g, 95.23%). m/z=183.2 [M+H]⁺, ¹H NMR (400 MHz, DMSO): δ8.38 (s, 1H), 7.24-7.21 (m, 1H), 6.63-6.59 (m, 1H), 6.18 (s, 2H), 4.23(s, 2H).

Step-6 Synthesis of 4-Chloro-7-bromoisoindolin-1-one (3.4)

To a suspension of 7-amino-4-chloroisoindolin-1-one (3.3) (100 g, 0.547mol) in HBr (47%, 500 mL) at −10° C. was added a solution of sodiumnitrite (75.5 g,1.09 mol) in water (500 mL). After stirring cold for 60min, copper (I) bromide (86.04 g, 0.60 mol) was added. After stirring at80° C. for 40 min, the reaction mixture was poured onto ice water. Theprecipitate collected by filtration, washed with water, and dried undervacuum to afford the title compound as a light brown solid (3.4) (120 g,89.55%). m/z=247.5 [M+H]⁺, ¹H NMR (400 MHz, DMSO): δ 9.02-8.96 (m, 1H),7.76-7.71 (m, 1H), 7.66-7.62 (m, 1H), 4.39-4.37 (m, 2H).

Step-7 Synthesis of tert-Butyl7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate (3.5)

To a solution of 4-chloro-7-bromoisoindolin-1-one (3.4) (120 g, 0.487mol) in THF at 0° C. (1500 mL) were added di-tert-butyl dicarbonate (159g, 0.731 mol) and DMAP (74 g,0.60 mol). After stirring at RT for 4 h,the mixture was diluted with EtOAc, washed with water and brine driedover Na₂SO₄, and concentrated in vacuum. The residue was purified bysilica gel chromatography (gradient: 0-2% EtOAc in DCM) to afford thetitle compound as a white solid (3.5) (130 g, 77.38%). MS (ES): m/z346.6, 348.6 [M]⁺,[M+2]⁺, ¹H NMR (400 MHz, CDCl₃): δ 7.62-7.58 (m, 1H),7.45-7.41 (m, 1H), 4.68 (s, 2H), 1.16 (s, 9H).

Step 5. tert-butyl4-chloro-7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(3.6)

A mixture of tert-butyl 7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate(3.5) (2 g, 5.77 mmol), tert-butyl4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (preparation describedin WO2015131080, 1.39 g, 7.21 mmol), Cs₂CO₃ (5.64 g, 17.31 mmol) andXantphos (0.40 g, 0.692 mmol) was stirred in dry 1,4-dioxane (8 mL) anddegassed under N2 stream. After 15 mins Pd₂(dba)₃ (0.53 g, 0.577 mmol)was added and the reaction was heated at 110° C. and stirred for 6 h.The reaction mixture was cooled to RT and then diluted ethyl acetate (25mL) and water (20 mL). The organic layer was collected, and the aqueousphase was extracted with ethyl acetate (2×25 mL), and the combinedorganic extracts were washed with brine (20 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography (0-20% gradient elution MeOH in DCM).The residue obtained was then triturated with diethyl ether and theresulting solid was collected by filtration to afford the title compound(3.6) (2.09 g, 79%) as a beige solid. m/z=458.2 [M+H]⁺, ¹H NMR (400 MHz,DMSO): δ 9.41-9.38 (m, 1H), 8.53 (d, J=9.1 Hz, 1H), 8.05-8.02 (m, 1H),7.66-7.61 (m, 1H), 7.52-7.46 (m, 1H), 7.08 (d, J=8.8 Hz, 1H), 4.75 (s,2H), 3.19-3.13 (m, 4H), 2.53-2.47 (m, 4H), 2.28 (s, 3H), 1.59 (s, 9H).

Step 6. tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(3.8)

To a degassed solution of tert-butyl3-bromo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (3.7) (300 mg, 1.01mmol) in 1,4-dioxane (6 mL) was added KOAc (297 mg, 3.03 mmol) andbis(pinacolato)diboron (282 mg, 1.11 mmol). The solution was purged witha N2 stream for 30 min before Pd(dppf)Cl₂ (37 mg, 0.051 mmol) was added,and the reaction was then stirred in a sealed tube at 125° C. overnight.The reaction mixture was cooled to RT and then diluted ethyl acetate (25mL) and water (20 mL). The organic layer was collected, and the aqueousphase was extracted with ethyl acetate (2×25 mL). The combined organiclayers were washed with brine (10 mL), then passed through a hydrophobicfrit and concentrated under reduced pressure. The crude compound (3.8)was taken forwards to the next step without purification.

Step 7. tert-butyl3-(2-(tert-butoxycarbonyl)-7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-1-oxoisoindolin-4-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(3.9)

A microwave vial was charged with tert-butyl4-chloro-7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(3.6) (100 mg, 0.218 mmol), tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(3.8) (113 mg, 0.328 mmol) and 1,4-dioxane/water (3 mL, 5:1 solution).K₃PO₄.H₂O (185 mg, 0.873 mmol) was added and the mixture was stirred atRT and purged with N2 for 15 mins before the catalyst XPhos Pd G2 (3.4mg, 10% mmol) was added. The reaction was heated at 150° C. for 15 minsin a Biotage Initiator® microwave. The mixture was diluted with EtOAc(10 mL) and washed with water (10 mL), saturated aqueous NaHCO₃ solution(10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentratedunder reduced pressure. The crude compound (3.9) was taken forwards tothe next step without purification.

Step 8.7-45-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-4-(1H-pyrrolo[3,2-b]pyridin-3-yl)isoindolin-1-one(I-26)

The residue (3.9) was dissolved in DCM (3 mL) and treated with TFA (100eq., 1.5 mL). The reaction was stirred for 30 mins at RT, and thenconcentrated under vacuum and triturated with 7N methanolic ammonia (2×3mL). The crude product was purified by preparative HPLC to afford thedesired compound (I-26) (10 mg, 15%) as a pale yellow solid. m/z=440.5[M+H]⁺, ¹H NMR (400 MHz, DMSO): δ 11.60 (d, J=2.5 Hz, 1H), 9.81 (s, 1H),8.75 (s, 1H), 8.49-8.41 (m, 3H), 8.01 (d, J=2.9 Hz, 1H), 7.91-7.84 (m,2H), 7.45 (dd, J=3.0, 8.9 Hz, 1H), 7.20 (dd, J=4.5, 8.2 Hz, 1H),6.98-6.94 (m, 1H), 4.63 (s, 2H), 3.20-3.14 (m, 4H), 2.71-2.68 (m, 4H),2.40 (s, 3H).

Example 4. Method E Synthesis of7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-4-(1H-pyrrolo[3,2-c]pyridin-3-yl)isoindolin-1-one(I-24)

Step 1: tert-butyl3-(2-(tert-butoxycarbonyl)-7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-1-oxoisoindolin-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate(4.1)

tert-Butyl3-(2-(tert-butoxycarbonyl)-745-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-1-oxoisoindolin-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate(4.1) was prepared from tert-butyl4-chloro-7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(3.6) and tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylatein a similar fashion to that described for7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-4-(1H-pyrrolo[3,2-b]pyridin-3-yl)isoindolin-1-one(I-26).

Step 2:7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-4-(1H-pyrrolo[3,2-c]pyridin-3-yl)isoindolin-1-one(I-24)

Compound 4.1 was diluted with DCM and treated with TFA (100 eq.). Thereaction was stirred for 30 mins at rt before the mixture wasconcentrated under vacuum and triturated with methanolic ammonia.Purified by prep. HPLC to afford the desired compound I-24. m/z=440[M+H]⁺, ¹H NMR (400 MHz, DMSO): δ 12.16-12.08 (m, 1H), 9.86 (s, 1H),8.80 (s, 1H), 8.57-8.54 (m, 1H), 8.31 (d, J=6.0 Hz, 1H), 8.15 (s, 1H),8.05 (d, J=2.9 Hz, 1H), 7.89-7.82 (m, 2H), 7.61 (d, J=5.9 Hz, 1H), 7.49(dd, J=3.0, 9.0 Hz, 1H), 7.00-6.97 (m, 1H), 4.56-4.54 (m, 2 H),3.20-3.14 (m, 4H), 2.71-2.68 (m, 4H), 2.62 (s, 3H).

Example 5. Method F Synthesis of4-(imidazo[1,2-a]pyridin-3-yl)-7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)isoindolin-1-one(I-39)

Step 1: tert-butyl4-(imidazo[1,2-a]pyridin-3-yl)-7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(5.1)

A 20 mL microwave vial was charged with 3.6 (150 mg, 0.328 mmol),bis(pinacolato)diboron (108 mg, 0.426 mmol), XPhos Pd G2 (2.6 mg, 0.003mmol), XPhos (1.55 mg, 0.003 mmol), solid K₃PO₄ (190 mg, 0.893 mmol) andEtOH (12 mL). The mixture was degassed, purged with N2, and stirred atRT overnight. 3-Bromoimidazo[1,2-1]pyridine, 3M K₃PO₄ (330 mL, 0.983mmol) and a portion of XPhos Pd G2 (2.6 mg, 0.003 mmol) and XPhos (1.55mg, 0.003 mmol) were added. The mixture degassed, purged with N2, andheated at 40° C. overnight. Loaded onto Biotage—ISOLUTE® HM-N andpurified by silica gel chromatography (0-25% gradient elution MeOH inDCM) to afford 5.1 as a yellow solid which was used in the next reactionwithout analysis.

Step 2:4-(imidazo[1,2-a]pyridin-3-yl)-7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)isoindolin-1-one(I-39)

tert-butyl4-(imidazo[1,2-a]pyridin-3-yl)-7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(5.1) was diluted with DCM (5 mL) and treated with TFA (100 eq., 1.8mL). The reaction was stirred for 30 mins at RT, and then concentratedunder vacuum and triturated with 7N methanolic ammonia (2×3 mL). Theresidue was purified by preparative HPLC to afford the desired compound(I-39) (41.3 mg, 89%). m/z=440.2 [M+H]⁺, ¹H NMR (400 MHz, DMSO): δ 9.86(s, 1H), 8.77 (s, 1H), 8.57 (d, J=8.5 Hz, 1H), 8.39 (d, J=6.9 Hz, 1H),8.01 (d, J=3.0 Hz, 1H), 7.84 (s, 1H), 7.69 (dd, J=8.8, 15.1 Hz, 2H),7.45 (dd, J=3.1, 9.0 Hz, 1H), 7.33-7.29 (m, 1H), 6.99-6.92 (m, 2H), 4.39(s, 2H), 3.12 (dd, J=4.9, 4.9 Hz, 4H), 2.48 (dd, J=4.9, 4.9 Hz, 4H),2.24 (s, 3H).

Example 6. Method G Synthesis of7-[[5-(4-methylpiperazin-1-yl)-2-pyridyl]amino]-4-(2-phenyl-1H-indol-3-yl)-2,3-dihydropyrrolo[3,4-c]pyridin-1-one(I-141)

Step 1:2-(2,4-dimethoxybenzyl)-7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-4-(phenylethynyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(6.1)

A mixture of 1.6 (350 mg, 0.69 mmol),bis(triphenylphosphine)palladium(II) chloride (48 mg, 0.07 mmol) andcopper(I) iodide (13 mg, 0.07 mmol) were placed under an atmosphere ofnitrogen, then suspended in THF (1 mL) and acetonitrile (2 mL). Themixture was treated with phenylacetylene (0.17 mL, 1.6 mmol) andtrimethylamine (0.24 mL, 1.8 mmol), and heated at 90° C. for 16 h. Thereaction was cooled to RT, charged with phenylacetylene (0.17 mL, 1.6mmol), bis(triphenylphosphine)palladium(II) chloride (48 mg, 0.07 mmol)and copper(I) iodide (13 mg, 0.07 mmol), and degassed with nitrogen. Thereaction was then heated at 90° C. for 6.5 h, then cooled to RT,quenched with water (15 mL), and extracted into DCM (4×20 mL). Thecombined organic layer was washed with brine (20 mL), passed through ahydrophobic frit, and concentrated under reduced pressure. The crudematerial was purified by silica gel chromatography eluting with 0-20% 7NNH₃ in MeOH/EtOAc to afford 6.1 (280 mg).

Step 2:2-(2,4-dimethoxybenzyl)-7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-4-(2-phenyl-1H-indol-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(6.2) and2-(2,4-dimethoxybenzyl)-7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-4-(3-phenyl-1H-indol-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(6.3)

A mixture of 2-iodoaniline (71 mg, 0.33 mmol), 6.1 (280 mg, 0.49 mmol),palladium(II) acetate (7 mg, 0.03 mmol),1,1′-bis(diphenylphosphino)ferrocene (27 mg, 0.05 mmol), potassiumacetate (159 mg, 1.6 mmol) and lithium chloride (14 mg, 0.33 mmol) wasplaced under an atmosphere of nitrogen. The mixture was dissolved inN-methyl-2-pyrrolidone (5 mL), and heated at 140° C. After 2 h, thereaction was charged with 2-iodoaniline (71 mg, 0.33 mmol) and heatingcontinued at 140° C. After 1.5 h, the reaction was charged withpalladium(II) acetate (7 mg, 0.03 mmol) and1,1′-bis(diphenylphosphino)ferrocene (27 mg, 0.05 mmol) and heatingcontinued at 140° C. After 45 min, the reaction was cooled to RT, andthe reaction mixture filtered through Celite®, washed with 5%MeOH/EtOAc, and the filtrate was partitioned between 4% aqueous lithiumchloride (100 mL) and 5% MeOH/EtOAc (3×75 mL). The combined organiclayer was washed with brine (2×100 mL), passed through a hydrophobicfilter and concentrated under reduced pressure. The residue was purifiedby silica gel chromatography eluting with 0-100% EtOAc/hexane, then0-20% (7N NH₃ in MeOH)/EtOAc to afford 6.2 and 6.3 as a 1:1 mixture ofinseparable regioisomers.

Step 3:7-((5-(4-Methylpiperazin-1-yl)pyridin-2-yl)amino)-4-(2-phenyl-1H-indol-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-141)

A solution of the mixture of 6.1 and 6.2 (181 mg, 0.14 mmol) in TFA (3mL) was heated by microwave at 150° C. for 15 min. The solvent wasremoved under reduced pressure, and the crude material was purified bypreparative HPLC to afford I-141 (5 mg, 8%) as a solid. m/z 516.4 [M+H]t¹H NMR (400 MHz, DMSO): δ 11.67 (s, 1H), 9.85 (s, 1H), 9.25 (s, 1H),8.70 (s, 1H), 8.04 (d, J=3.3 Hz, 1H), 7.53-7.37 (m, 7H), 7.33 (tt,J=1.9, 7.0 Hz, 1H), 7.17 (dt, J=1.2, 7.6 Hz, 1H), 7.06-7.01 (m, 2H),3.66 (s, 2H), 3.24-3.17 (m, 4H), 2.81-2.72 (m, 4H), 2.43 (s, 3H).

Example 7. Method H Synthesis of5-chloro-7-[[5-(4-hydroxy-1-piperidyl)-2-pyridyl]amino]-4-(1-methylpyrrolo[2,3-b]pyridin-4-yl)isoindolin-1-one(I-190)

Step 1: 3-Hydroxy-4-nitroisoindolin-1-one (7.2)

A solution of 3-nitrophthalimide (7.1) (5.00 g, 26 mmol) in methanol (50mL) and DCM (50 mL) was treated portion wise with sodium borohydride(0.98 g, 26 mmol), and the reaction was stirred at RT for 4 h. Thereaction was quenched with saturated aqueous sodium bicarbonate (40 mL),stirred for 20 min, then the organic phase was separated. The aqueousphase was extracted with EtOAc (2×50 mL). The combine organic layer waswashed with brine (50 mL), dried over MgSO4, filtered, and concentratedunder reduced pressure to afford 7.2 (3.51 g, 70%) as a yellow solid.Material used in next step without purification.

Step 2: 4-Nitroisoindolin-1-one (7.3)

A suspension of 7.2 (3.51 g, 18 mmol) in DCM (60 mL) was treated withTFA (12.5 mL, 163 mmol), and the resulting solution was stirred at RTfor 10 min, followed by dropwise addition of triethylsilane (4.3 mL, 27mmol), and the reaction was stirred at RT for 4 h. The solvent wasremoved under reduced pressure, and the residue taken up in MeOH,basified with 7N NH₃ in MeOH, and the solvent was again removed underreduced pressure. The crude material was purified by silica gelchromatography eluting with 0-100% EtOAc/hexane, and then 0-25%MeOH/EtOAc to afford 7.3 (5.46 g.). ¹H NMR (400 MHz, DMSO): δ 9.05 (s,1H), 8.49 (dd, J=0.8, 8.1 Hz, 1H), 8.17 (dd, J=0.7, 7.5 Hz, 1H), 7.86(t, J=7.8 Hz, 1H), 4.85 (s, 2H), 1.30-1.12 (m, 0H).

Step 3: 4-Aminoisoindolin-1-one (7.4)

A solution of 7.3 (5.46 g, 31 mmol) in degassed ethanol (100 mL) wastreated with 10% Pd/C (33 mg, 0.31 mmol), placed under an atmosphere ofhydrogen, and stirred at RT for 4 h. The reaction mixture was thenfiltered over Celite® and the filtrate was concentrated under reducedpressure. The crude material was purified by silica gel chromatographyeluting with 0-20% (7N NH₃ in MeOH)/EtOAc to afford 7.4 (1.57 g, 35%) asa yellow solid. ¹H NMR (400 MHz, DMSO): δ 8.35 (s, 1H), 7.16 (t, J=7.6Hz, 1H), 6.86 (dd, J=0.9, 7.5 Hz, 1H), 6.76 (dd, J=1.0, 7.8 Hz, 1H),5.38 (s, 2H), 4.13 (s, 2H).

Step 4: 4-Amino-7-bromoisoindolin-1-one (7.5)

A solution of 7.4 (1.57 g, 11 mmol) in methanol (25 mL) and THF (30 mL)was treated portion wise with N-bromosuccinimide (1.89 g, 11 mmol), andthe reaction was stirred at RT for 1.5 h. The reaction was quenched withwater (50 mL), then the organic solvent was removed under reducedpressure. The resulting precipitate was collected by filtration, washedwith water, then azeotroped with toluene (20 mL). The crude material waspurified by reverse phase chromatography using 0-50% Acetonitrile/(10 mMaqueous ammonium bicarbonate to afford 7.5 (735 mg, 31%) as an off-whitesolid.

Step 5: 4-Amino-7-bromo-5-chloroisoindolin-1-one (7.6)

A solution of 7.5 (735 mg, 3.2 mmol) in methanol (8 mL) and THF (9 mL)was treated portion wise with N-chlorosuccinimide (454 mg, 3.4 mmol),and the reaction was stirred at RT for 1 h, then heated at reflux for1.5 h. The reaction was cooled to RT, and quenched with water (10 mL),then the organic solvent was removed under reduced pressure. The solidswere collected by filtration, washed with water, then dissolved in 25%MeOH/EtOAc, dried over MgSO4, filtered, and concentrated under reducedpressure to afford 7.6 (966 mg) as a black solid. ¹H NMR (400 MHz,DMSO): δ 8.67 (s, 1H), 7.52 (s, 1H), 5.85 (s, 2H), 4.18 (s, 2H).

Step 6: 7-Bromo-5-chloro-4-iodoisoindolin-1-one (7.7)

A mixture of 7.6 (966 mg, 3.7 mmol) in conc. hydrochloric acid (0.4 mL,13 mmol) and water (10 mL) was cooled to 0° C., and treated carefullywith sulfuric acid (5 mL, 94 mmol). The resulting slurry was stirred at0° C. and treated dropwise over 10 min with a solution of sodium nitrite(280 mg, 4.1 mmol) in water (5 mL). The reaction was stirred at 0° C.for 1 h, then treated dropwise with a solution of potassium iodide (1230mg, 7.4 mmol) in water (5 mL). The reaction was allowed to stir and warmto RT for 1.5 h, then the reaction mixture was poured onto an ice/watermix, and the solids collected by filtration. The solid was dissolved in25% MeOH/EtOAc, dried over MgSO4, filtered, and concentrated underreduced pressure to afford 7.7 (600 mg, 43%) as a black solid. ¹H NMR(400 MHz, DMSO): δ 9.02 (s, 1H), 7.97 (s, 1H), 4.23 (s, 2H).

Step 7: tert-Butyl7-bromo-5-chloro-4-iodo-1-oxoisoindoline-2-carboxylate (7.8)

A mixture of 7.7 (600 mg, 1.6 mmol) and DMAP (256 mg, 2.1 mmol) in THF(10 mL) was treated with di-tert-butyl dicarbonate (0.4 mL, 1.7 mmol)and stirred at RT for 4 h. The reaction was quenched with saturatedaqueous sodium bicarbonate (20 mL) and extracted into EtOAc (3×40 mL).The combined organic layer was washed with brine (40 mL), passed througha hydrophobic filter and concentrated under reduced pressure. The crudematerial was dissolved in minimal MeOH, triturated with diethyl ether,and the solids were collected by filtration to afford 7.8 (389 mg, 51%)as a black solid. ¹H NMR (400 MHz, DMSO): δ 8.06 (s, 1H), 4.57 (s, 2H),1.59 (s, 9H).

Step 8, 9 and 10 were carried out following representative proceduresdescribed in Example 2 and Example 3 to afford I-190 (4 mg, 16%) as anoff-white solid. m/z 489.3 (³⁵Cl), 491.4 (³⁷Cl) [M+H]⁺. ¹H NMR (400 MHz,DMSO): δ 9.78 (s, 1H), 8.74 (s, 2H), 8.36 (d, J=4.9 Hz, 1H), 8.07 (d,J=3.1 Hz, 1H), 7.57 (d, J=3.1 Hz, 1H), 7.46 (dd, J=3.1, 9.0 Hz, 1H),7.14 (d, J=4.9 Hz, 1H), 6.97-6.94 (m, 1H), 6.21 (d, J=3.5 Hz, 1H), 4.71(d, J=3.6 Hz, 1H), 4.20 (d, J=18.2 Hz, 1H), 3.95 (d, J=18.0 Hz, 1H),3.88 (s, 3H), 3.68-3.60 (m, 1H), 3.50 (td, J=4.4, 12.2 Hz, 2H), 2.85(ddd, J=2.8, 10.0, 12.5 Hz, 2H), 1.88-1.81 (m, 2H), 1.61-1.46 (m, 2H).

Example 8. Method I Synthesis of5-fluoro-7-[[5-(4-hydroxy-1-piperidyl)-2-pyridyl]amino]-4-(1-methylpyrrolo[2,3-b]pyridin-4-yl)isoindolin-1-one(I-197)

Step 1: Methyl 2-bromo-6-(bromomethyl)-4-fluorobenzoate (8.2)

A mixture of methyl 2-bromo-4-fluoro-6-methylbenzoate 8.1 (1.00 g, 4.05mmol), NBS (0.94 g, 5.26 mmol and benzoyl peroxide (98 mg, 0.405 mmol)in CCl₄ (5 mL) was heated at 75° C. in a sealed tube overnight. Themixture was filtered through Celite washing with DCM and concentratedunder vacuum. Purified by silica gel chromatography eluting with 0-25%EtOAc in cyclohexane to afford the title compound 8.2 (1.32 g, quant.)as a pale yellow oil.

Step 2: 7-Bromo-5-fluoroisoindolin-1-one (8.3)

A solution of methyl 2-bromo-6-(bromomethyl)-4-fluorobenzoate 8.2 (1.32g, 4.05 mmol) in 7N NH₃/MeOH (10 mL) was stirred at RT for 3 h. Themixture was concentrated in vacuo and the residue triturated with Et₂Oto leave the title compound 8.3 (711 mg, 75%) as a white solid. ¹H NMR(400 MHz, DMSO): δ 8.74 (s, 1H), 7.64-7.61 (m, 1H), 7.53-7.49 (m, 1H),4.35 (s, 2H).

Step 3: 7-Bromo-5-fluoro-4-nitroisoindolin-1-one (8.4)

A solution of 7-bromo-5-fluoroisoindolin-1-one 8.3 (460 mg, 2.00 mmol)in c.H₂SO₄ (3 mL) at 0° C. was treated with potassium nitrate (138 mg,3.00 mmol). Stirred cold for 1 h then allowed to warm to RT overnight.The mixture was poured onto ice/water and the precipitate collected byfiltration washing with water to leave the title compound 8.4 (438 mg,80%) as a pale yellow solid.

Step 4: 4-Amino-7-bromo-5-fluoroisoindolin-1-one (8.5)

A mixture of 7-bromo-5-fluoro-4-nitroisoindolin-1-one 8.4 (530 mg, 1.93mmol), iron powder (323 mg, 5.78 mmol) and ammonium chloride (515 mg,9.64 mmol) in EtOH (10 mL) and water (2 mL) was heated at reflux for 2h. The hot mixture was filtered through Celite washing with 25% MeOH inDCM. The filtrate was concentrated under vacuum and triturated withwater. Collected by filtration washing with water. The residue wasloaded onto HMN and purified by silica gel chromatography eluting with50-100% EtOAc in DCM to afford the title compound 8.5 (176 mg, 37%) as acream coloured solid. ¹H NMR (400 MHz, DMSO): δ 8.58-8.55 (m, 2H), 7.35(d, J=11.0 Hz, 2H), 5.63 (s, 4H), 4.13-4.12 (m, 4H), 3.18 (d, J=5.3 Hz,1H).

Step 5: 4-Iodo-7-bromo-5-fluoroisoindolin-1-one (8.6)

A solution of 4-amino-7-bromo-5-fluoroisoindolin-1-one 8.5 (300 mg, 1.22mmol) in 20% sulfuric acid (5 mL) was cooled to 0° C., treated dropwisewith a solution of sodium nitrite (169 mg, 2.45 mmol) in water (1 mL)and stirred cold for 1 h. A solution of potassium iodide (406 mg, 2.45mmol) in water (1 mL) was added dropwise. After the addition, themixture was stirred at RT for 1 h. Poured onto ice/water and theprecipitate was collected by filtration. Washed with water and dried toleave the title compound 8.6 (137 mg, 31%) as an orange solid. Theaqueous phase was extracted with EtOAc (3×), dried over Na₂SO₄ andconcentrated in vacuo to leave additional title compound 8.6 (207 mg,47%) as an orange solid. ¹H NMR (400 MHz, DMSO): δ 8.93 (s, 1H),7.70-7.67 (m, 1H), 4.19 (s, 2H)

Step 6: tert-Butyl7-bromo-5-fluoro-4-iodo-1-oxoisoindoline-2-carboxylate (8.7)

A solution of 4-iodo-7-bromo-5-fluoroisoindolin-1-one 8.6 (340 mg, 0.955mmol) in THF (10 mL) was treated with di-tert-butyl dicarbonate (240 mg,1.10 mmol) and DMAP (140 mg, 1.15 mmol) was stirred at RT for 18 h. Themixture was diluted with EtOAc, washed with water and brine, dried overNa₂SO₄, and concentrated in vacuo. Purified by silica gel chromatography(gradient: 0-80% EtOAc in cyclohexane) afforded the title compound 8.7(344 mg, 79%) as an off-white solid.

¹H NMR (400 MHz, CDCl₃): δ 7.38 (d, J=7.7 Hz, 1H), 4.54 (s, 2H), 1.62(s, 9H).

Step 7, 8 and 9 were carried out following representative proceduresdescribed in Example 2 and Example 3 to afford I-197 (40 mg, 71%) as apale yellow solid. m/z=473 [M+H]⁺.

¹H NMR (400 MHz, DMSO): δ 9.91 (d, J=1.3 Hz, 1H), 8.72 (s, 1H), 8.46 (d,J=14.1 Hz, 1H), 8.35-8.33 (m, 1H), 8.05 (d, J=3.0 Hz, 1H), 7.57 (d,J=3.5 Hz, 1H), 7.46 (dd, J=3.0, 9.0 Hz, 1H), 7.24 (d, J=4.9 Hz, 1H),6.98-6.95 (m, 1H), 6.29 (dd, J=2.5, 3.4 Hz, 1H), 4.71 (d, J=4.2 Hz, 1H),4.29 (br s, 2H), 3.87 (s, 3H), 3.71-3.59 (m, 1H), 3.53-3.44 (m, 2H),2.88-2.80 (m, 2H), 1.89-1.81 (m, 2H), 1.58-1.47 (m, 2H).

Example 9. Method J Synthesis ofS)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-45-(2-(2-hydroxypropan-2-yl)morpholino)pyridin-2-yl)amino)isoindolin-1-one(I-344) &(R)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-(2-(2-hydroxypropan-2-yl)morpholino)pyridin-2-yl)amino)isoindolin-1-one(I-345)

Step 1: tert-butyl4-chloro-7-((5-(2-(2-hydroxypropan-2-yl)morpholino)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(9.2)

tert-butyl4-chloro-7-((5-(2-(2-hydroxypropan-2-yl)morpholino)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(9.2) was prepared from tert-butyl7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate (3.5) and2-(4-(6-aminopyridin-3-yl)morpholin-2-yl)propan-2-ol (9.1) in a similarfashion to that described tert-butyl4-chloro-7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(3.6).

Step 2. tert-butyl7-45-(2-(2-hydroxypropan-2-yl)morpholino)pyridin-2-yl)amino)-1-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate(9.3)

A 30 mL microwave vial was charged with 9.2 (800 mg, 1.38 mmol),bis(pinacolato)diboron (1.4 g, 5.54 mmol), XPhos Pd G2 (120 mg, 0.13mmol), XPhos (80 mg, 0.13 mmol), solid K₃PO₄ (587 mg, 2.6 mmol) andDioxane (12 mL). The mixture was degassed, purged with N2, and stirredat 100° C. for 3 h. The reaction mixture was cooled to RT and thendiluted ethyl acetate (100 mL) and water (100 mL). The organic layer wascollected, and the aqueous phase was extracted with ethyl acetate (2×100mL), and the combined organic extracts were washed with brine (100 mL),dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by column chromatography (0-20% gradientelution MeOH in DCM). The residue obtained was then triturated withpentane and the resulting solid was collected by filtration to affordthe title compound 9.3 (700 mg, 74%)

Step 3. tert-butyl4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-(2-(2-hydroxypropan-2-yl)morpholino)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(9.5)

A 30 mL microwave vial was charged with 9.3 (500 mg, 0.84 mmol),7-fluoro-3-iodoimidazo[1,2-a]pyridine (9.4) (330 mg, 1.26 mmol), XPhosPd G2 (40 mg, 0.08 mmol), XPhos (66 mg, 0.08 mmol), solid K₃PO₄ (356 mg,1.6 mmol), dioxane (10 mL) and water (2 mL). The mixture was degassed,purged with N2, and stirred at 100° C. for 3 h. The reaction mixture wascooled to RT and then diluted ethyl acetate (50 mL) and water (50 mL).The organic layer was collected, and the aqueous phase was extractedwith ethyl acetate (2×50 mL), and the combined organic extracts werewashed with brine (50 mL), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by columnchromatography (0-5% gradient elution MeOH in DCM). The residue obtainedwas then triturated with pentane and the resulting solid was collectedby filtration to afford the title compound (9.5) (240 mg, 47%)

Step 4.4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-(2-(2-hydroxypropan-2-yl)morpholino)pyridin-2-yl)amino)isoindolin-1-one(9.6)

tert-butyl4-(imidazo[1,2-a]pyridin-3-yl)-7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(9.5) (250 mg, 0.41 mmol) was diluted with DCM (5 mL) and treated withTFA (100 eq., 3.3 mL). The reaction was stirred for 30 mins at RT, andThe reaction mixture was transferred into saturated sodium bicarbonatesolution (100 mL), extracted with DCM (2×50 mL) the combined organiclayer was washed with brine (50 mL), dried with MgSO4 and thenconcentrated in vacuo. The residue was purified by preparative HPLC toafford the desired compound (9.6) (100 mg, 48%). m/z=440.2 [M+H]⁺.

Step 5.S)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-(2-(2-hydroxypropan-2-yl)morpholino)pyridin-2-yl)amino)isoindolin-1-one(I-344) &(R)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-(2-(2-hydroxypropan-2-yl)morpholino)pyridin-2-yl)amino)isoindolin-1-one(I-345)

9.6 was separated on Shimadzu LC-20AP and UV detector. The column usedwas CHIRALPAK IBN-5 (250*21.0) mm, 5 micron, column flow was 18.0mL/min. Mobile phase were used (A) 0.1% DEA IN Acetonitrile (B) 0.1% DEAIN Methanol. The UV spectra were recorded at 308 nm Lambda max by ChiralSFC to afford compounds I-344 (23 mg) and I-345 (24 mg).

I-344: ¹H NMR (400 MHz, DMSO): δ 9.87 (s, 1H), 8.80 (s, 1H), 8.58-8.55(m, 1H), 8.42 (s, 1H), 8.00 (s, 1H), 7.81-7.86 (m, 1H), 7.70-7.67 (m,1H), 7.53-7.43 (m, 2H), 6.99-6.96 (m, 2H), 4.50 (s, 1H), 4.37 (s, 2H),4.00-3.98 (d, J=10.8 Hz, 1H), 3.67-3.57 (m, 2H), 3.46 (m, 2H), 3.39-3.33(m, 3H), 1.21-1.09 (m, 6H)

I-345: ¹H NMR (400 MHz, DMSO): δ 9.87 (s, 1H), 8.80 (s, 1H), 8.58-8.56(d, J=8.8 Hz, 1H), 8.44-8.40 (t, J=16, 1H), 8.01 (s, 1H), 7.81 (s, 1H),7.70-7.68 (d, J=8.8, 1H), 7.54-7.51 (d, J=9.6 Hz, 1H), 7.46-7.44 (m,1H), 6.99-6.95 (m, 2H), 4.51 (s, 1H), 4.37 (s, 2H), 4.00-3.98 (d, J=10.8Hz, 1H), 3.67-3.57 (m, 2H), 3.46-3.44 (m, 2H), 3.34-3.19 (m, 3H),1.23-1.06 (m, 6H).

Example 10. Method K Synthesis of3,3-dimethyl-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-((5-(piperazin-1-yl)pyridin-2-yl)amino)isoindolin-1-one(I-273)

Step 1. methyl 2-bromo-3-chlorobenzoate (10.2)

A mixture of 2-bromo-3-chlorobenzoic acid (10.1) (10.0 g, 42.9 mmol) inDMF (100 mL) were added K₂CO₃ (11.8 g, 85.8 mmol) and CH₃I (3.96 mL,63.0 mmol) and stirred at RT for 2 h. The reaction mixture wastransferred into water (500 mL) and extracted with ethyl acetate (2×500mL) and the combined organic phases were washed with brine (500 mL),dried with MgSO4, filtered, and then concentrated in vacuo. The residuewas purified by column chromatography (0-50% gradient elution EtOAc iniso-hexane) to afford the title compound 10.2 (10 g, 95.14%). m/z 247.1[M+H]⁺.

Step 2. methyl 3-chloro-2-cyanobenzoate (10.3)

A solution of methyl 2-bromo-3-chlorobenzoate (10.2) (0.5 g, 2.008 mmol)in DMF (5 mL) were added CuCN (0.197 g, 2.2 mmol) and reaction mixturewere heated at 90° C. temperature for 1.2 h. The reaction mixture wastransferred into water (50 mL) and extracted with ethyl acetate (2×50mL) and the combined organic phases were washed with brine (50 mL),dried with MgSO4, filtered, and then concentrated in vacuo. The residuewas purified by column chromatography (0-50% gradient elution EtOAc iniso-hexane) to afford the title compound 10.3 (0.25 g, 63.61%). m/z 195[M+H]⁺.

Step 3. 4-chloro-3,3-dimethylisoindolin-1-one (10.4)

A solution of methyl 3-chloro-2-cyanobenzoate (10.3) (0.60 g, 3.07 mmol)in dry THF (10 mL) at −78° C. under a nitrogen atmosphere was treateddropwise with CH₃Li (1M solution in THF, 12.3 mL, 12.3 mmol). After theaddition, the mixture was allowed to warm to RT and stirred for 2 h. Thereaction mixture was transferred into water (100 mL), extracted withethyl acetate (2×50 mL) the combined organic layer was washed with brine(50 mL), dried with MgSO4, and then concentrated in vacuo. The residuewas purified by column chromatography (0-70% gradient elution EtOAc iniso-hexane) to afford the title compound 10.4 (0.5 g 83.33%). m/z 196[M+H]⁺

Step 4. 4-chloro-3,3-dimethyl-7-nitroisoindolin-1-one (10.5)

4-chloro-3,3-dimethyl-7-nitroisoindolin-1-one (10.5) was prepared from4-chloro-3,3-dimethylisoindolin-1-one (10.4) in a similar fashion tothat described 4-Chloro-7-nitroisoindolin-1-one (3.2) (400 mg, 59.17%).m/z 241 [M+H]⁺.

Step 5. tert-butyl7-chloro-1,1-dimethyl-4-nitro-3-oxoisoindoline-2-carboxylate (10.6)

To a solution of 4-chloro-3,3-dimethyl-7-nitroisoindolin-1-one (10.5)(0.5 g, 2.08 mmol) in THF (20 mL) was added di-tert-butyl dicarbonate(681 mg, 3.1 mmol) and DMAP (254 mg, 2.08 mmol) at 0° C. The reactionwas stirred at RT for 1 h. The solution was diluted with ethyl acetate(50 mL) and water (25 mL). The organic phase was collected, and theaqueous phase was extracted with ethyl acetate (2×50 mL). The combinedorganic layers were washed with brine (30 mL), dried over MgSO4,filtered, and concentrated under reduced pressure. The crude compoundwas purified by column chromatography (0-50% gradient elution EtOAc iniso-hexanes) to afford the title compound 10.6 (49 mg, 69.20%). m/z 341[M+H]⁺.

Step 6. tert-butyl4-amino-7-chloro-1,1-dimethyl-3-oxoisoindoline-2-carboxylate (10.7)

A solution tert-butyl7-chloro-1,1-dimethyl-4-nitro-3-oxoisoindoline-2-carboxylate (10.6) (0.5g, 1.46 mmol) in THF (5 mL) was treated with Raney nickel (100 mg) underhydrogen atmosphere and stirred at RT for 30 min. Reaction mass wasfilter through celite bed, and washed with ethyl acetate (2×50 mL). Thecombined organic solvent was removed in vacuo to afford the titlecompound (10.7) (400 mg, 87.91%). m/z 310 [M+H]⁺.

Step 7. tert-butyl4-((5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)-7-chloro-1,1-dimethyl-3-oxoisoindoline-2-carboxylate(10.8)

To a solution of tert-butyl4-amino-7-chloro-1,1-dimethyl-3-oxoisoindoline-2-carboxylate (10.7) (462mg, 1.49 mmol) in 1,4-dioxane (10 mL) was added tert-butyl4-(6-bromopyridin-3-yl)piperazine-1-carboxylate (509 mg, 1.49 mmol) andCS₂CO₃ (971 mg, 2.98 mmol). The reaction mixture was degassed underargon for 20 min, and Pd₂(dba)₃ (136 mg, 0.14 mmol,) and Xanthphos (172mg, 0.29 mmol) was added and then heated at 100° C. for 2 h. Thesolution was diluted with ethyl acetate (50 mL) and water (50 mL). Theorganic phase was collected, and the aqueous phase was extracted withethyl acetate (2×50 mL). The combined organic layers were washed withbrine (30 mL), dried over MgSO4, filtered, and concentrated underreduced pressure. The crude compound was purified by columnchromatography (0-70% gradient elution EtOAc in iso-hexanes) to affordthe title compound 10.8 (210 mg, 38.57%). m/z 572.3 [M+H]⁺.

Step 8. tert-butyl4-((5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)-1,1-dimethyl-7-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-oxoisoindoline-2-carboxylate(10.9)

To a solution of tert-butyl44(5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)-7-chloro-1,1-dimethyl-3-oxoisoindoline-2-carboxylate(10.8) (60 mg, 0.10 mmol) in 1,4-dioxane (2 mL) was added1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(35 mg, 0.136 mmol) and K₃PO₄ (44 mg, 0.21 mmol) was added. The reactionmixture was degassed under argon for 20 min, and Xphos (8 mg, 0.015mmol) and XphosPdG2 (13 mg, 0.0157 mmol) were added and then heated at110° C. for 1 h. The solution was diluted with ethyl acetate (25 mL) andwater (25 mL). The organic phase was collected, and the aqueous phasewas extracted with ethyl acetate (2×25 mL). The combined organic layerswere washed with brine (20 mL), dried over MgSO4, filtered, andconcentrated under reduced pressure. The crude compound was purified bycolumn chromatography (0-70% gradient elution EtOAc in iso-hexanes) toafford the title compound 10.9 (36 mg, 51.42%), m/z 668.4[M+H]⁺.

Step 9.3,3-dimethyl-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-45-(piperazin-1-yl)pyridin-2-yl)amino)isoindolin-1-one(I-273)

tert-butyl4-((5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)-1,1-dimethyl-7-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-oxoisoindoline-2-carboxylate(10.9) (36 mg, 0.41 mmol) was diluted with DCM (5 mL) and treated withTFA (100 eq., 3.3 mL). The reaction was stirred for 30 mins at RT, andthen concentrated under vacuum and triturated with 7N methanolic ammonia(2×3 mL). The residue was purified by preparative HPLC to afford thedesired compound (I-273) (20 mg, 79%), m/z 468.2 [M+H]+]+, ¹H NMR (400MHz, DMSO): δ 9.98 (s, 1H), 8.77 (s, 1H), 8.44-8.42 (d, J=8 Hz, 1H),8.31-8.27 (m, 2H), 7.98-7.97 (s, 1H), 7.51-7.50 (m, 1H), 7.44-7.42 (d,J=8 Hz, 1H), 7.22-7.20 (d, J=8 Hz, 1H), 7.01-7.00 (d, J=4 Hz, 1H),6.95-6.93 (d, J=8 Hz, 1H), 6.05-6.04 (m, 1H), 3.86 (s, 1H), 3.098 (s,1H), 2.97 (s, 1H), 1.14 (s, 6H).

Example 11. Method L Synthesis ofS)-7-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-3-methyl-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)isoindolin-1-one(I-286) and((R)-7-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-3-methyl-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)isoindolin-1-one(I-287)

Step 1. 4-chloro-2-(2,4-dimethoxybenzyl)isoindolin-1-one (11.2)

To a solution of methyl 2-(bromomethyl)-3-chlorobenzoate (11.1) (10 g,37.1 mmol) in methanol (100 mL) was added 2,4-dimethoxybenzylamine (7.6g, 45.53 mmol) and N,N-Diisopropylethylamine (14.6 g, 113.84 mmol) at 0°C. The reaction mixture was stirred at RT for 1 h. The solution wasdiluted with ethyl acetate (500 mL) and water (500 mL). The organicphase was collected, and the aqueous phase was extracted with ethylacetate (2×500 mL). The combined organic layers were washed with brine(500 mL), dried over MgSO4, filtered, and concentrated under reducedpressure. The crude compound was purified by column chromatography(0-20% gradient elution EtOAc in iso-hexanes) to afford the titlecompound 11.2 (11. g, 91.22%), m/z 318.7 [M+H]⁺

Step 2. 4-chloro-2-(2,4-dimethoxybenzyl)-3-methylisoindolin-1-one (11.3)

To a solution of 4-chloro-2-(2,4-dimethoxybenzyl)isoindolin-1-one (11.2)(8 g, 25.2 mmol) in N, N′-DMF (100 mL) was added sodium hydride (60%dispersion in mineral oil, 1.2 g, 30.28 mmol,) at 0° C. and stirred atsame temperature for 15 min. Then methyl iodide (3.9 g, 27.76 mmol) wasadded dropwise over 15 min. The reaction mixture was stirred at RT for 1h. The solution was poured onto ice-cold water (500 mL) and theprecipitate was collected by filtration. The solid was washed with waterand dried in vacuo to afford the title compound 11.3 (8.0 g, 95.77%).m/z 332.8 [M+H]⁺

Step 3. 4-chloro-3-methylisoindolin-1-one (11.4)

A solution of compound4-chloro-2-(2,4-dimethoxybenzyl)-3-methylisoindolin-1-one (11.3) (8.0 g,24.11 mmol) and trifluoroacetic acid (80 mL) heated at 60° C. for 1 h.The reaction mixture was quenched with saturated solution of sodiumbicarbonate (500 mL) and extracted with Ethyl acetate (3×500 mL). Thecombined organic layer was washed with brine solution, and the combinedorganic layers were washed with brine (500 mL), dried over MgSO4,filtered, and concentrated under reduced pressure. The crude compoundwas purified by column chromatography (0-60% gradient elution EtOAc iniso-hexanes) to afford the title compound 11.4 (4 g, 91.34%). m/z 182.5[M+H]⁺.

Step 4. 4-chloro-3-methyl-7-nitroisoindolin-1-one (11.5)

4-chloro-3-methyl-7-nitroisoindolin-1-one (11.5) was prepared from4-chloro-3-methylisoindolin-1-one (11.4) in a similar fashion to thatdescribed 4-Chloro-7-nitroisoindolin-1-one (3.2). (3.4 g, 68.12%). m/z227.5 [M+H]⁺.

Step 5. tert-butyl4-chloro-3-methyl-7-nitro-1-oxoisoindoline-2-carboxylate (11.6)

tert-butyl 4-chloro-3-methyl-7-nitro-1-oxoisoindoline-2-carboxylate(11.6) was prepared from 4-chloro-3-methyl-7-nitroisoindolin-1-one(11.5) in a similar fashion to that described tert-butyl7-chloro-1,1-dimethyl-4-nitro-3-oxoisoindoline-2-carboxylate (10.6) (3.2g, 65.28%). m/z 327.6 [M+H]⁺.

Step 6. tert-butyl4-amino-7-chloro-1-methyl-3-oxoisoindoline-2-carboxylate (11.7)

tert-butyl 4-amino-7-chloro-1-methyl-3-oxoisoindoline-2-carboxylate(11.7) was prepared from tert-butyl4-chloro-3-methyl-7-nitro-1-oxoisoindoline-2-carboxylate (11.6) in asimilar fashion to that described tert-butyl4-amino-7-chloro-1,1-dimethyl-3-oxoisoindoline-2-carboxylate (10.7) (2.3g 79.14%). m/z 297.6 [M+H]⁺

Step 7. tert-butyl4-chloro-7-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-3-methyl-1-oxoisoindoline-2-carboxylate(11.8)

tert-butyl4-chloro-7-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-3-methyl-1-oxoisoindoline-2-carboxylate(11.8) was prepared from tert-butyl4-amino-7-chloro-1-methyl-3-oxoisoindoline-2-carboxylate (11.7) and1-(6-bromopyridin-3-yl)piperidin-4-ol in a similar fashion to thatdescribed tert-butyl4-((5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)-7-chloro-1,1-dimethyl-3-oxoisoindoline-2-carboxylate(10.9) (1.5 g, 47%). m/z 473.4 [M+H]⁺

Step 8. tert-butyl4-45-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-1-methyl-7-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-oxoisoindoline-2-carboxylate(11.9)

tert-butyl4-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-1-methyl-7-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-oxoisoindoline-2-carboxylate(11.9) was prepared from tert-butyl4-chloro-7-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-3-methyl-1-oxoisoindoline-2-carboxylate(11.8) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridinein a similar fashion to that described tert-butyl445-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)-1,1-dimethyl-7-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-oxoisoindoline-2-carboxylate(10.11) (0.3 g, Yield: 55.45%). m/z 569.5 [M+H]⁺.

Step 9.7-45-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-3-methyl-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)isoindolin-1-one(11.10)

7-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-3-methyl-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)isoindolin-1-one(11.10) was prepared from tert-butyl4-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-1-methyl-7-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-oxoisoindoline-2-carboxylate(11.9) in a similar fashion to that described3,3-dimethyl-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-((5-(piperazin-1-yl)pyridin-2-yl)amino)isoindolin-1-one(I-273) (0.13 g, Yield: 65.74%). m/z 469.7 [M+H]⁺.

Step 10.(S)-7-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-3-methyl-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)isoindolin-1-one(I-286) and((R)-7-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-3-methyl-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)isoindolin-1-one(I-287)

11.10 was separated on Waters SFC 200 and UV detector. The column wasused CHIRALCEL OJ-H (250*21.0) mm, 5 micron, column flow was 80.0 mL/minand ABPR was 100 bar. Mobile phase were used (A) Liquid Carbon dioxide(Liq. CO2) and (B) 0.1% DEA In propanol:acetonitrile (50:50) to providecompounds I-286 (35 mg) and I-287 (35 mg).

I-286: m/z 469.7 [M+H]⁺. ¹H NMR (400 MHz, DMSO): δ 9.905 (s, 1H), 8.809(s, 1H), 8.51-8.49 (d, J=8 Hz, 1H), 8.32-8.30 (m, 1H), 8.00 (s, 1H),7.60-7.57 (m, 2H), 7.45-7.43 (m, 1H), 7.25-7.24 (m, 1H), 6.95-6.93 (d,J=8, 1H), 6.42-6.41 (m, 1H), 5.05-5.04 (m, 1H), 4.724 (s, 1H), 3.882 (s,3H), 3.628 (s, 1H), 3.47-3.44 (m, 3H), 2.84-2.79 (t, J=20, 2H),1.86-1.83 (m, 2H), 1.55-1.51 (m, 2H), 0.80-0.78 (m, 3H)

I-287: m/z 469.7 [M+H]⁺. ¹H NMR (400 MHz, DMSO): δ 9.90 (s, 1H), 8.80(s, 1H), 8.51-8.49 (d, J=8 Hz, 1H), 8.32-8.31 (m, 1H), 8.01 (s, 1H),7.60-7.57 (m, 2H), 7.45-7.43 (m, 1H), 7.25-7.24 (m, 1H), 6.95-6.93 (d,J=8, 1H), 6.42-6.41 (m, 1H), 5.05-5.04 (m, 1H), 4.72 (s, 1H), 3.88 (s,3H), 3.63 (s, 1H), 3.47-3.44 (m, 3H), 2.84-2.79 (t, J=20, 2H), 1.86-1.84(m, 2H), 1.53-1.51 (m, 2H), 0.80-0.79 (m, 3H).

Example 12. Method M Synthesis of-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-5-methyl-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)isoindolin-1-one:(I-292)

Step 1. 3-chloro-2,4-dimethylbenzoic Acid (12.2)

To a solution of 2,4-dimethylbenzoic acid (12.1) (20 g, 133.17 mmol) inTFA (400 mL) was added NCS (26.67 g, 199.73 mmol, 1.5 eq), and stirredat 50° C. for 16 h. The reaction mixture was quenched with saturatedsolution of sodium bicarbonate (1000 mL) and extracted with Ethylacetate (3×500 mL). The combined organic layer was washed with brinesolution (500 mL), dried over MgSO4, filtered, and concentrated underreduced pressure. The crude compound was purified by columnchromatography (0-60% gradient elution EtOAc in iso-hexanes) to affordthe title compound (12.2) (7 g, 48.37%). m/z 185.2 [M+H]⁺.

Step 2. methyl 3-chloro-2,4-dimethylbenzoate (12.3)

To a solution of 3-chloro-2,4-dimethylbenzoic acid (12.2) (12 g, 65.21mmol) in DMF (120 mL) was added K₂CO₃ (22.4 g, 163.0 mmol), and methyliodide (13.8 g, 163.0 mmol). The reaction was stirred at RT for 3 h. Thesolution was diluted with ethyl acetate (500 mL) and water (500 mL). Theorganic phase was collected, and the aqueous phase was extracted withethyl acetate (2×500 mL). The combined organic layers were washed withbrine (500 mL), dried over MgSO₄, filtered, and concentrated underreduced pressure. The crude compound was purified by columnchromatography (0-20% gradient elution EtOAc in iso-hexanes) to affordthe title compound 12.3 (11 g, 85.27%). m/z 199.7 [M+H]⁺

Step 3. methyl 2-(bromomethyl)-3-chloro-4-methylbenzoate (12.4)

To a solution of methyl 3-chloro-2,4-dimethylbenzoate (12.3) (11 g,55.55 mmol) in CCl₄ (110 mL) was added NBS (9.88 g,55.5 mmol), and DPPO(124 mg, 0.55 mmol). The reaction was stirred at 90° C. for 5 h. Thesolution was diluted with ethyl acetate (500 mL) and water (500 mL). Theorganic phase was collected, and the aqueous phase was extracted withethyl acetate (2×500 mL). The combined organic layers were washed withbrine (500 mL), dried over MgSO4, filtered, and concentrated underreduced pressure to afford the title compound 12.4 (14 g). The crudecompound was used as such for next step.

Step 4. 4-chloro-5-methylisoindolin-1-one (12.5)

To a solution of methyl 2-(bromomethyl)-3-chloro-4-methylbenzoate (12.4)(14 g, 50.73 mmol) in methanol was added ammonia (7N in methanol, 500mL) at 0° C., and the reaction was stirred at RT for 16 h. Aftercompletion of reaction, solvent was evaporated under vacuum to affordcrude material. Crude material which was purified by trituration usingpentane and hexane to provide compound 4-chloro-5-methylisoindolin-1-one(12.5) (8 g) m/z 182 [M+H]⁺.

Step 6 to Step 10 were carried out following representative proceduresdescribed in Example 5. 1-292 (40 mg) m/z 467.6 ¹H NMR (400 MHz, DMSO):δ 9.55 (s, 1H), 8.35-8.34 (d, J=4.8 Hz, 1H), 8.26 (s, 1H), 8.19 (s, 1H),8.03-8.03 (s, 1H), 7.49-7.49 (d, J=3.2 Hz, 1H), 7.43-7.40 (m, 1H),7.04-7.03 (m, 1H), 6.96-6.94 (m, 1H), 6.12-6.11 (m, 1H), 4.44 (s, 1H),4.10-4.06 (d, J=18 Hz, 1H), 3.89 (s, 3H), 3.63 (s, 1H), 3.84 (s, 1H),3.67 (s, 1H), 3.48-3.45 (m, 2H), 2.90-2.86 (t, J=19.2, 2H), 2.15 (s,3H), 1.87 (s, 2H), 1.57-1.55 (m, 2H).

Example 14. Method 0 Synthesis of4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-((5-((methylsulfonyl)methyl)pyridin-2-yl)amino)isoindolin-1-one(I-293)

Step 1. tert-butyl 4-chloro-7-nitro-1-oxoisoindoline-2-carboxylate(14.1)

A mixture of 4-chloro-7-nitroisoindolin-1-one (3.2) (5.00 g, 23.53 mmol)in 1,4-dioxane (50 mL) was added Boc-anhydride (7.69 g, 35.29 mmol), TEA(7.1 g 9.8 mL, 70.58 mmol) and DMAP (0.28 g, 2.35 mmol) at rt. Thereaction was stirred for 30 min at rt. The reaction mixture was dilutedwith Water (300 mL). The mixture was extracted with ethyl acetate (3×250mL) and the combined organic phases were washed with brine (100 mL),dried with Na₂SO₄, filtered, and then concentrated in vacuo. The residuewas triturated with hexanes and n-pentane to afford the title compound(14.1) (7.3 g, 99.2%) as off white solid. m/z=313.5 [M+H]⁺,

Step 2. tert-butyl4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-nitro-1-oxoisoindoline-2-carboxylate(14.2)

A solution of tert-butyl 4-chloro-7-nitro-1-oxoisoindoline-2-carboxylate(14.1) (1.0 g, 3.2 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(0.9 g, 3.52 mmol) in 1,4-dioxane:Water (9:1) (25 mL) was added tribasicpotassium phosphate (2.0 g, 9.60 mmol). The reaction mixture wasdegassed with argon gas for 10 min. X-phos Pd G2 (0.13 g, 0.16 mmol) wasadded into reaction mixture the reaction was stirred for 30 min at 110°C. The reaction mixture was diluted with Water (80 mL). The mixture wasextracted with ethyl acetate (3×100 mL) and the combined organic phaseswere washed with brine (80 mL), dried with Na₂SO₄, filtered, and thenconcentrated in vacuo. The residue was purified by column chromatography(0-10% gradient elution EtOAc in Hexanes) to afford the title compound14.2 (0.91 g, 68.9%) as light yellow solid. m/z=409.3 [M+H]⁺,

Step 3. tert-butyl7-amino-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-oxoisoindoline-2-carboxylate(14.3)

To a solution of tert-butyl4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-nitro-1-oxoisoindoline-2-carboxylate(14.2) (0.8 g, 1.96 mmol) in THF (30 mL) was added Raney nickel (0.4 g,50% w/w). The reaction was purged with H2 gas for 2 h. The slurry wasfiltered off under vacuum filtration and celite bed was washed withmethanol (80 mL). The solvent was removed in vacuo to yield the titlecompound (14.3) (0.7 g, 94.43%) as an off white solid. m/z=379.2 [M+H]⁺

Step 4. tert-butyl4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-((5-((methylsulfonyl)methyl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(14.4)

To a solution of tert-butyl7-amino-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-oxoisoindoline-2-carboxylate(14.3) (0.5 g, 1.32 mmol) in dry 1,4-dioxane (10 mL) was added Cs₂CO₃(0.85 g, 2.64 mmol) followed by2-chloro-5-((methylsulfonyl)methyl)pyridine (0.27 g, 1.32 mmol). Themixture was purged with an argon stream for 10 min before Xantphos (76mg, 0.132 mmol) and Pd₂(dba)₃ (121 mg, 0.132 mmol) were added. Themixture was degassed for 10 more min. The reaction was then stirred at120° C. for 4 h. After cooling to RT, the reaction mixture was pouredinto saturated Water (80 mL). The mixture was extracted with ethylacetate (2×80 mL). The combined organic phases were washed with brine(25 mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The crude product was purified by column chromatography (0-25%gradient elution EtOAc in Hexanes) to afford the desired compound 14.4(0.22 g, 30.4%) as a yellow solid. m/z=548.5 [M+H]⁺

Step 5. Synthesis of4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-((5-((methylsulfonyl)methyl)pyridin-2-yl)amino)isoindolin-1-one(I-293)

A solution of tert-butyl4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-((5-((methylsulfonyl)methyl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(14.4) (0.135 g, 0.2 mmol) was dissolved in DCM (2.0 mL) and 4M HCl indioxane (1 mL) added under nitrogen atmosphere. The reaction mixture wasstirred at RT for 30 min. After completion of reaction, the reactionmixture was diluted with water and basified using saturated sodiumbicarbonate solution then extracted with DCM (3×30 mL). The combineorganic layer washed with brine solution, dried over sodium sulfate, andconcentrated under reduced pressure to afford crude material. Theresidue was purified by column chromatography eluting with 3-4% MeOH inDCM to afford I-293 (0.045 g, 33.33%) MS (ES): 448 m/z [M+H]+, ¹H NMR(400 MHz, DMSO): δ 10.298 (s, 1H), 8.872 (s, 1H), 8.74-8.72 (d, J=8.6Hz, 1H), 8.33 (s, 2H), 7.80-7.73 (m, 2H), 7.60 (s, 1H), 7.29-7.28 (m,1H), 7.10-7.07 (d, J=8.6 Hz, 1H), 6.49 (s, 1H), 4.49 (s, 1H), 3.8 8 (s,1H), 2.96 (s, 3H).

Example 16. Method Q Synthesis of7-bromo-4-chloro-2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4c]pyridin-1-one(I-289)

Step 1. 5-bromo-2-chloro-3-methylisonicotinic acid (16.2)

A solution of 5-bromo-2-chloro-3-methylpyridine (16.1) (2.5 g, 12.135mmol) in THF (20 mL) was cooled at −78° C. under a nitrogen atmosphere,and was treated dropwise with lithium diisopropyl amide (2M solution inTHF, 6.6 mL, 13.34 mmol). After the addition, the mixture was stirredfor 30 min. then purged with CO2 gas for 30 min. The mixture was allowedto warm to RT and stirred for 45 min. The reaction mixture was combinedwith 48 other batch on the same scale prepared by an identical method.The mixture was quenched with saturated NaHCO₃ solution (25 mL) andextracted EtOAc (3×20 mL). Aqueous layer wash was neutralized byHydrochloric acid till PH-4 and extracted by 30% isopropyl alcohol inchloroform. The combined extract was dried over sodium sulfate andconcentrated under vacuum to leave the title compound 16.2 (79.87 g,53.7%) as white solid material. m/z 250.5 [M+H]⁺

Step 2. methyl 5-bromo-2-chloro-3-methylisonicotinate (16.3)

To a solution of 5-bromo-2-chloro-3-methylisonicotinic acid (16.2) (20g, 80.0 mmol) in dry DMF (200 mL) at RT under a nitrogen atmosphere wasadded potassium carbonate (22.08 g, 160.0 mmol) and methyl Iodide (17.02g, 120.0 mmol) dropwise. After the addition, the mixture was stirred atRT for 16 h. The reaction mixture was combined with 3 other batches onthe same scale prepared by an identical method. The mixture was quenchedwith water and extracted with ethyl acetate (2×25 mL) and the combinedorganic phases were washed with brine (20 mL), dried with MgSO4,filtered, and then concentrated in vacuo. The residue was purified bycolumn chromatography (0-2% gradient elution EtOAc in iso-hexane) toafford the title compound 16.3 (65 g, 76.94%) as colorless oil. m/z265.5 [M+H]⁺

Step 3. methyl 5-bromo-3-(bromomethyl)-2-chloroisonicotinate (16.4)

A solution of methyl 5-bromo-2-chloro-3-methylisonicotinate (16.3) (10g, 37.87 mmol) in carbon tetrachloride (90 mL) was treated with N-bromosuccinimide (13.4 g, 75.75 mmol), followed by azobisisobutyronitrile(0.62 g, 3.787 mmol). The resulting mixture was heated at 80° C. for 16h. The reaction mixture was combined with 5 other batches on the samescale prepared by an identical method. After completion of reaction thesolvent was eliminated under vacuum and the residue was purified bycolumn chromatography (0-2% gradient elution EtOAc in iso-hexane) toafford the title compound 16.4 (75 g, 96.28%) as white solid. m/z 344[M+H]⁺.

Step 4.7-bromo-4-chloro-2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-oneSynthesis of Compound (1.7)

To a solution of methyl 5-bromo-3-(bromomethyl)-2-chloroisonicotinate16.4 (18 g, 61.64 mmol) in methanol (70 mL) was added N,N-Diisopropylethylamine (35.2 g, 272.7 mmol) and2,4-Dimethoxybenzylamine (12 g, 74.99 mmol). The reaction mixturestirred at RT for 30 min. The reaction mixture was combined with 3 otherbatches on the same scale prepared by an identical method. The reactionwas filtered, and the residue was washed with methanol and dried undervacuum to afford the title compound 1.7 (80 g, 95.95%) as a white solid.m/z 397 [M+1]⁺.

Synthesis of7-45-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-289)

Step 5, 6 and 7 were carried out following representative proceduresdescribed in Example 1. (45 mg), m/z 453.5, ¹H NMR (400 MHz, DMSO): δ9.86 (s, 1H), 9.42 (s, 1H), 9.14 (s, 1H), 8.36-8.34 (m, 1H), 7.84 (s,1H), 7.57-7.56 (m, 1H), 7.38-7.37 (m, 1H), 7.20-7.17 (m, 1H), 7.07-7.05(d, J=8 Hz, 1H), 6.92-6.92 (m, 1H), 4.72 (s, 2H), 4.64-4.61 (d, J=12 Hz,2H), 3.88 (s, 3H), 3.77-3.70 (dd, J=22.5 Hz, 2H), 3.57-3.55 (d, J=8 Hz,1H), 3.00-2.98 (d, J=8 Hz, 1H), 1.97-1.94 (d, J=12 Hz, 1H), 1.88-1.86(d, J=8 Hz, 1H).

Example 17. Method R Synthesis of7-((5-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-309)

Step 1. 7-bromo-4-chloro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(17.1)

To a stirred solution of methyl5-bromo-3-(bromomethyl)-2-chloroisonicotinate (16.4) (18 g, 61.64 mmol)in methanol (70 mL) was purged ammonia gas at 0° C. After 1 h solidprecipitate was observed in the reaction mixture. The reaction mixturewas combined with 3 other batches on the same scale prepared by anidentical method. The reaction mixture was filtered. The residue waswash with methanol and dried under vacuum to afford 17.1 (36 g, 69.38%)as brown solid. MS (ES) m/z 247-249 [M+2]⁺

Step 2. tert-butyl7-bromo-4-chloro-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(17.2)

To a solution of7-bromo-4-chloro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (17.1) (5 g,20.24 mmol) in dioxane (250 mL) were added Dimethyl amino pyridine (0.24g, 2.024 mmol) and Boc anhydride (5.0 g, 23.27 mmol) at RT. The reactionmixture stirred at RT for 1 h. Solid precipitate was dissolve inreaction mixture. The reaction mixture was combined with 13 otherbatches on the same scale prepared by an identical method. The reactionwas diluted with water (750 mL) and extracted by ethyl acetate (3×500mL). The combined organic layer dried over sodium sulfate andconcentrate under vacuum to afford residue was purified by columnchromatography (0-5% gradient elution EtOAc in iso-hexane) to afford thetitle compound 17.2 (40 g, 79.11%) as a white solid MS (ES): m/z 347-349[M+2]⁺.

Step 3 and 4 were carried out following representative proceduresdescribed in Example 1 to afford 17.4.

Step 5.7-((5-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-309)

To a solution of tert-butyl7-((5-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate17.4 (0.120 g, 0.2 mmol) into DCM (3 mL) was added HCl in dioxane (3 mL)at 0° C. The reaction mixture was stirred at RT for 1 h. Aftercompletion of reaction, the reaction mixture was concentrated underreduced pressure to afford crude which was purified by columnchromatography to afford the title compound I-309 (0.056 g, 56.98%) as awhite solid. MS (ES): m/z 454.52 (M+H). ¹H NMR (400 MHz, DMSO): δ 9.85(s, 1H), 9.41 (s, 1H), 9.13 (s, 1H), 8.34-8.33 (m, 1H), 7.83-7.82 (m,1H), 7.56-7.55 (m, 1H), 7.37-7.35 (m, 1H), 7.19-7.16 (m, 1H), 7.05-7.03(d, J=8 Hz, 1H), 6.91-6.90 (m, 1H), 4.70 (s, 2H), 4.62-4.59 (d, J=12 Hz,2H), 3.86 (s, 3H), 3.76-3.74 (d, J=8 Hz, 1H), 3.70-3.68 (d, J=8 Hz, 1H),3.55-3.53 (d, J=8 Hz, 1H), 2.98-2.96 (d, J=8 Hz, 1H), 1.95-1.93 (d, J=8Hz, 1H) 1.87-1.84 (d, J=12 Hz, 1H).

Example 18. Method S Synthesis of7-45-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-4-(imidazo[1,2-a]pyrazin-5-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-376)

Step 1. tert-butyl7-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-4-(imidazo[1,2-a]pyrazin-5-yl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(18.2)

To a mixture of tert-butyl4-chloro-7-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(18.1) (prepared according to Example 1) (0.500 g, 1.0 mmol) and5-bromoimidazo[1,2-a]pyrazine (0.256 g, 1.3 mmol) in 1,4-dioxane (20 mL)was added hexametylditin (0.534 g, 1.6 mmol, 1.5 eq) at RT. The reactionmixture was degassed using nitrogen gas for 20 mins.tetrakis(triphenylphosphine)-palladium(O) (0.062 g, 0.05 mmol, 0.05 eq)was added to the reaction mixture and stirred at 100° C. for 48 h. Thereaction mixture was diluted with Water (60 mL). The mixture wasextracted with ethyl acetate (3×80 mL) and the combined organic phaseswere washed with brine (80 mL), dried with Na₂SO₄, filtered, and thenconcentrated in vacuo. The residue was purified by column chromatography(0-4% methanol gradient in DCM) and then was purified by prep HPLC toafford to afford the title compound (18.2) (0.04 g, 6.78%) as off whitesolid. LCMS: 100% m/z=542 [M+H]⁺

Step 2.7-45-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-4-(imidazo[1,2-a]pyrazin-5-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-376)

To a solution of tert-butyl745-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-4-(imidazo[1,2-a]pyrazin-5-yl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(18.2) (0.040 g, 0.07 mmol) in DCM (3 mL) was added TFA (1.0 mL). Thereaction was stirred for 1 h at RT. After completion of reaction, thereaction mixture was diluted with water and basified using saturatedsodium bicarbonate solution, then extracted with DCM (3×30 mL). Thecombined organic layer was washed with brine solution, dried over sodiumsulfate and the solvent was removed in vacuo. The residue was purifiedvia prep HPLC (0.1% TFA in water and 100% acetonitrile) to afford I-376(0.015 g, 31.79%) MS (ES): 442 m/z [M+H]+, ¹H NMR (400 MHz, DMSO): δ9.94 (s, 1H), 9.76-9.75 (m, 1H), 9.44 (s, 1H), 9.30 (s, 1H), 9.21 (s,1H), 8.29 (s, 1H), 8.07-8.05 (m, 2H), 7.48-7.45 (m, 1H), 7.04-7.02 (d,J=8 Hz, 1H), 4.80 (s, 2H), 4.72-4.70 (m, 1H), 3.63 (s, 1H), 3.46-3.38(m, 2H), 2.86-2.81 (t, J=8 Hz, 2H), 1.84 (s, 2H), 1.53-1.51 (m, 2H).

Example 19. Method T Synthesis of7-((5-((3R,4R)-4-fluoro-3-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-4-(imidazo[1,2-a]pyrazin-3-yl)isoindolin-1-one(I-434) &7-((5-((3S,4S)-4-fluoro-3-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-4-(imidazo[1,2-a]pyrazin-3-yl)isoindolin-1-one(I-435)

Racemic tert-butyl7-((5-((3,4)-4-fluoro-3-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-4-(imidazo[1,2-a]pyrazin-3-yl)-1-oxoisoindoline-2-carboxylate(19.1)

Compound 19.1 was synthesized in a similar fashion to that described inExample 9.

Step 1 synthesis of tert-butyl7-((5-((3r,4r)-4-fluoro-3-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-4-(imidazo[1,2-a]pyrazin-3-yl)-1-oxoisoindoline-2-carboxylate(19.2) and tert-butyl7-((5-((3S,4S)-4-fluoro-3-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-4-(imidazo[1,2-a]pyrazin-3-yl)-1-oxoisoindoline-2-carboxylate(19.3)

19.1 (250 mg) were separated by Chiral SFC-Shimadzu LC-20AP and UVdetector. The column used was CHIRALPAK IC (250*21.0) mm, 5 micron,column flow was 20 mL/min. Mobile phase used: (A) 0.1% DEA IN n-Hexane,(B) 0.1% DEA In propanol:acetonitrile (70:30), to provide compounds 19.2(100 mg) and 19.3 (110 mg).

Step 2:7-((5-((3R,4R)-4-fluoro-3-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-4-(imidazo[1,2-a]pyrazin-3-yl)isoindolin-1-one(I-434)

To a solution of tert-butyl7-((5-((3R,4R)-4-fluoro-3-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-4-(imidazo[1,2-a]pyrazin-3-yl)-1-oxoisoindoline-2-carboxylate(19.2) (0.100 g, 0.1 mmol) in DCM (3 mL) was added HCl in dioxane (3 mL)at 0° C. The reaction mixture was stirred at RT for 1 h. The reactionmixture was neutralized using saturated sodium bicarbonate solution,then extracted with 10% methanol in DCM (3×30 mL) and the combinedorganic layers were concentrated under reduced pressure to afford crude,which was purified by column chromatography to provide the titlecompound I-434 (0.030 g, 36.54%) as a white solid. MS (ES): m/z 460.52(M+H). ¹H NMR (400 MHz, DMSO): δ 9.90 (s, 1H), 9.15-9.15 (m, 1H), 8.82(s, 1H), 8.60-8.58 (d, J=8 Hz, 1H), 8.48-8.46 (m, 1H), 8.12 (s, 1H),8.04-8.03 (d, J=4 Hz, 1H), 7.93-7.91 (d, J=8 Hz, 1H), 7.78-7.76 (d, J=8Hz, 1H), 7.49-7.46 (dd, J=8.8 Hz, 12 Hz, 1H), 6.99-6.97 (d, J=8 Hz, 1H),5.43 (s, 1H), 4.53-4.34 (m, 3H), 3.71-3.64 (m, 1H), 3.61-3.52 (m, 2H),2.86-2.81 (m, 1H), 2.69-2.63 (m, 1H), 2.16-2.10 (m, 1H) 1.78-1.74 (m,1H).

Step 2a:7-45-((3S,4S)-4-fluoro-3-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-4-(imidazo[1,2-a]pyrazin-3-yl)isoindolin-1-one(I-435)

To a solution of tert-butyl7-((5-((3S,4S)-4-fluoro-3-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-4-(imidazo[1,2-a]pyrazin-3-yl)-1-oxoisoindoline-2-carboxylate(19.3) (0.100 g, 0.1 mmol) into DCM (3 mL) was added HCl in dioxane (3mL) at 0° C. The reaction mixture was stirred at RT for 1 h. Thereaction mixture was neutralized using saturated sodium bicarbonatesolution, then extracted with DCM (3×30 mL) and the combined organiclayers were concentrated under reduced pressure to afford crude whichwas purified by column chromatography to provide the title compoundI-435 (0.042 g, yield-5154%) as a white solid. MS (ES): m/z 460.52(M+H). ¹H NMR (400 MHz, DMSO): δ 9.91 (s, 1H), 9.15 (s, 1H), 8.83 (s,1H), 8.60-8.58 (d, J=8 Hz, 1H), 8.48-8.46 (m, 1H), 8.16 (s, 1H),8.12-8.10 (d, J=8 Hz, 1H), 8.04-8.03 (d, J=4 Hz, 1H), 7.93-7.91 (d, J=8Hz, 1H), 7.78-7.76 (d, J=8 Hz, 1H), 7.49-7.46 (dd, J=8 Hz, 8 Hz, 1H),4.51 (s, 1H), 4.510-4.35 (m, 3H), 3.71-3.64 (m, 1H), 3.60-3.53 (m, 2H),2.86-2.81 (m, 1H), 2.68-2.63 (m, 1H), 2.15-2.09 (m, 1H) 1.78-1.74 (m,1H).

Example 20. Method U Synthesis of4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-((7-methyl-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)amino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-418)

Step 1. tert-butyl7-(benzylamino)-4-chloro-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(20.1)

To a solution of tert-butyl7-bromo-4-chloro-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(17.2) (3 g, 8.6 mmol) in dry toluene (40 mL) was added K₂CO₃ (3.7 g,26.06 mmol) followed by phenylmethanamine (1.02 g, 9.54 mmol). Themixture was purged with a N2 stream for 10 min before Xantphos (1.0 g,1.704 mmol) and Pd₂(dba)₃(0.794 g, 0.86 mmol) were added. The mixturewas degassed for 10 more min. The reaction was then stirred at 120° C.for 2 h. After cooling to RT, the reaction mixture was poured intosaturated aqueous NH₄C1 solution (30 mL) and filtered through a CelitePad. The mixture was extracted with ethyl acetate (2×25 mL). Thecombined organic phases were washed with brine (25 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The crudeproduct was purified by column chromatography (0-10% gradient elutionEtOAc in iso-hexane) to afford the desired compound (20.1) (1.8 g,46.49%) as a white solid. m/z=374.1 [M+H]⁺,

Step 2. tert-butyl7-(benzylamino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(20.2)

To a solution of tert-butyl 7-(benzylamino)-4-chloro-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(20.1) (1.8 g, 4.9 mmol) and1-methyl-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(1.9 g, 7.4 mmol) in 1,4-dioxane:Water (9:1) (25 mL) was added tribasicpotassium phosphate (3.14 g, 14.80 mmol). The reaction mixture wasdegassed with argon gas for 10 min. X-phos Pd G2 (0.194 g, 0.26 mmol)was added into reaction mixture. The reaction was stirred for 30 min at110° C. The reaction mixture was diluted with Water (80 mL). The mixturewas extracted with ethyl acetate (3×100 mL) and the combined organicphases were washed with brine (80 mL), dried with Na₂SO₄, filtered, andthen concentrated in vacuo. The residue was purified by columnchromatography (0-10% methanol gradient in DCM) to afford the titlecompound 20.2 (1.5 g, 66.7%) as light yellow solid. m/z=470.3 [M+H]⁺,

Step 3.7-amino-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(20.3)

A solution of compound tert-butyl7-(benzylamino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(20.2) (1.5 g, 3.11 mmol) in DCM (10 mL) and trifluoroacetic acid (5 mL)was added at 0° C. The reaction mixture was stirred at RT for 1 h. Thereaction mixture was quenched with saturated solution of sodiumbicarbonate (200 mL) and the precipitate was collected by filtration.The solid was washed with water and dried in vacuo to afford the titlecompound 20.3 (0.6 g, 67.54%). m/z 280.30 [M+H]⁺.

Step 4. tert-butyl2-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-7-yl)amino)-5,8-dihydro-1,7-naphthyridine-7(611)-carboxylate(20.4)

To a solution of7-amino-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(20.3) (0.6 g,2.15 mmol) in dry DMF (18 mL) was added K₃PO₄ (1.3 g, 6.40mmol) followed by tert-butyl2-chloro-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (0.690 g, 2.54mmol). The mixture was purged with a N2 stream for 10 min then BrettPhosPd G3 (0.136 g, 0.150 mmol) was added into reaction mixture. The mixturewas degassed for 10 more min. The reaction was then stirred at 120° C.for 2 h. After cooling to RT, the reaction mixture was poured intosaturated aqueous NH₄C1 solution (30 mL) and filtered through a CelitePad. The mixture was extracted with ethyl acetate (2×25 mL). Thecombined organic phases were washed with brine (25 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The crudeproduct was purified by column chromatography (0-10% gradient elutionEtOAc in iso-hexane) to afford the desired compound 20.4 (0.25 g, 22.7%)as a white solid. m/z=512.1 [M+H]⁺,

Step 5. tert-butyl2-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-7-yl)amino)-5,8-dihydro-1,7-naphthyridine-7(611)-carboxylate(I-413)

To a solution of tert-butyl2-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-7-yl)amino)-5,8-dihydro-1, 7-naphthyridine-7(6H)-carboxylate (20.4) (0.250 g, 0.48mmol) into DCM (3 mL) was added HCl in dioxane (3 mL) at 0° C. Thereaction mixture was stirred at RT for 1 h. The reaction mixture wasquenched with saturated solution of sodium bicarbonate (200 mL) and theprecipitate was collected by filtration. The solid was washed with waterand dried in vacuo to afford residue which was purified by columnchromatography (0-2% methanol gradient in DCM) to afford the titlecompound I-413 (0.125 g, yield-62.54%) as a white solid. MS (ES): m/z460.52 (M+H). ¹H NMR (400 MHz, DMSO): δ 8.38-8.24 (m, 3H), 7.59-7.54 (m,2H), 7.33-7.32 (d, J=4 Hz, 1H), 6.79 (s, 1H), 6.66 (s, 2H), 5.16 (s,2H), 3.87-3.81 (m, 5H), 2.95 (s, 2H), 2.70 (s, 2H).

Step 6.4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-((7-methyl-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)amino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-418)

To a solution of tert-butyl24(4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-7-yl)amino)-5,8-dihydro-1, 7-naphthyridine-7(6H)-carboxylate (I-413) (0.1 g, 3.11mmol) in methanol (10 mL) was added formaldehyde (3.7 g, 26.06 mmol).The mixture was stirred for 30 min. Acetic acid (1.0 g, 1.704 mmol) andsodium cyanoborohydride (0.794 g, 0.86 mmol) were added. The reactionwas then stirred at RT for 30 min. The reaction mixture was neutralizedusing saturated sodium bicarbonate solution then extracted with DCM(3×30 mL), and the combined organic layers were concentrated underreduced pressure to afford the residue, which was purified by columnchromatography (0-2% methanol gradient in DCM) to afford the titlecompound I-418 (0.03 g, 30.1%) as white solid. m/z=426.3 [M+H]⁺, ¹H NMR(400 MHz, DMSO): δ 8.39-8.38 (d, J=4 Hz, 1H), 8.32-8.30 (m, 2H),7.67-7.65 (d, J=8 Hz, 1H), 7.56-7.55 (d, J=4 Hz, 1H), 7.33-7.32 (d, J=4Hz, 1H), 6.81-6.80 (d, J=4 Hz, 1H), 6.69 (s, 2H), 5.17 (s, 2H), 3.88 (s,3H), 3.64 (s, 2H), 2.85-2.84 (m, 2H), 2.77 (s, 2H), 2.47 (s, 3H).

Example 21. Method Sp Synthesis ofR)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-478) and(S)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-479)

Step-1 Synthesis of compound tert-butyl4-chloro-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(21.1)

To a solution of tert-butyl7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate (3.5) (100 g, 289.0mmol) in 1-4 dioxane (1000 mL) were added Intermediate AA145 (63.95 g,289.0 mmol) and cesium carbonate (281 g, 867.0 mmol, 3.0 eq) at RT.After degassing with flow of nitrogen for 20 min,4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (33.46 g, 57.0 mmol, 0.2eq) and tris(dibenzylideneacetone)dipalladium(O) (26.44 g, 28.0 mmol,0.1 eq) were added. After stirring at 90° C. for 2 h, the reaction wascooled to RT; filtered through celite bed and washed with ethyl acetate(700 mL). The organic layer was washed with water (500 mL), dried overNa₂SO₄. and concentrated under reduced pressure. The residue waspurified by silica gel chromatography eluting with 1.5% to 2.7% MeOH/DCMto afford 21.1 (69 g, 49.03%) as orange solid. MS (ES): m/z 487.52[M+1]⁺, 1H NMR (400 MHz, DMSO-d6) δ 7.34-7.31 (d, J=8.4 Hz, 1H),6.37-6.35 (d, J=8 Hz, 1H), 5.71 (s, 2H), 3.97-3.85 (m, 2H), 3.76-367 (m,2H), 3.42-3.36 (m, 2H), 2.12 (s, 8H), 1.83-1.74 (m, 1H).

Step-2 Synthesis of compound tert-butyl7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-1-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate21.2

To a solution of the 21.1 (58 g, 119.0 mmol) suspended in 1-4 dioxane(580 mL) was added bis(pinacolato)diboron (60.50 g, 238.0 mmol, 2.0 eq)and potassium acetate (35.01 g, 357.0 mmol, 3.0 eq). After degassingwith flow of nitrogen for 20 min, XPhos PdG2 (9.36 g, 11.0 mmol, 0.1 eq)was added. After stirring at 90° C. for 2 h, the reaction was cooled toRT, filtered through celite and the celite bed was washed with ethylacetate (2 L). The combined organic layer was washed with water (500mL), dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography eluting with 3.0% to15% MeOH/DCM. The material was then triturated by hexanes to afford 21.2(54 g, 78.37%) as brown solid. MS (ES): m/z 579.54 [M+1]⁺.

Step-3 Synthesis of compound tert-butyl7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate21.3

To a solution of the 21.2 (45 g, 77.0 mmol) and7-fluoro-3-iodoimidazo[1,2-a]pyridine Intermediate BB63 (24.47 g, 93.0mmol, 1.2 eq) in 1-4 dioxane (360 mL) and water (90 mL) was addedpotassium phosphate tribasic (49.51 g, 233.0 mmol, 3.0 eq). Afterdegassing with flow of nitrogen for 20 min, XPhos PdG2 (6.11 g, 7.7mmol, 0.1 eq) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl(1.85 g, 3.8 mmol, 0.05 eq) were added. After stirring at 100° C. for 3h, the reaction was cooled to RT, filtered through celite bed and thecelite bed was washed with ethyl acetate (300 mL). The organic layer wasseparated and concentrated under reduced pressure. The residue waspurified by silica gel chromatography eluting with 2% to 3% MeOH/DCM.The isolated material was then triturated with diethyl ether to afford21.3 (26.66 g, 58.42%) as light yellow solid. MS (ES): m/z 587.20[M+1]⁺, 1H NMR (400 MHz, DMSO-d6) δ 9.76 (S, 1H), 8.83-8.81 (d, J=8.4Hz, 1H), 8.42-8.39 (t, J=12.8 Hz, 1H), 7.83-7.80 (d, J=12 Hz, 2H),7.70-7.68 (d, J=8.8 Hz, 1H), 7.08-7.06 (d, J=8.4 Hz, 1H), 7.00-6.98 (t,J=8 Hz, 1H), 4.73 (S, 2H), 3.96 (m, 2H), 3.82-3.80 (t, J=7.6 Hz, 2H),3.66-3.50 (m, 3H), 3.17-3.16 (d, J=5.2 Hz, 2H), 2.3 (S, 6H), 1.92-1.87(m, 1H), 1.51 (S, 9H).

Step-4 Chiral Separation

21.3 (30 g racemic) were separated on Shimadzu LC-20AP and UV detectorusing Chiralpak IC (250*21.0) mm, 5 micron, at 20.0 mL/min. Mobilephases were (A) 0.1% Diethylamine in n-Hexane (B) 0.1% Diethylamine inPropane-2-ol: Acetonitrile (70:30). to afford compounds 21.4 (10 g) and21.5 (9 g). Stereochemistry arbitrary assign.

Step-5a Synthesis ofR)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-478)

To a solution of 21.4 (10 g, 17.15 mmol) in DCM (100 mL) was added 4Mhydrochloric acid in 1-4 dioxane (40 mL) at RT. After stirring at 50° C.for 2 h, the reaction mixture was evaporated in vacuum and pH adjustwith NaHCO₃ solution to neutral. The aqueous layer was extracted with15% MeOH/DCM. The solvent was evaporated under reduced pressure andmaterial was triturated with diethyl ether to afford I-478 (7.3 g,88.02%) as light yellow solid. MS (ES): m/z 486.55. [M+1]⁺. 1H NMR (400MHz, DMSO-d6) δ 10.05 (S, 1H), 8.77-8.75 (d, J=8.8 Hz, 2H), 8.47-8.43(t, J=13.2 Hz, 1H), 7.82 (S, 1H), 7.74-7.72 (dd, J=28 Hz 2H), 6.99-6.93(dd, J=8 Hz 2H), 4.39 (S, 2H), 4.01-3.97 (m, 2H), 3.83-3.78 (m, 2H),3.64 (S, 3H), 3.54-3.50 (m, 4H), 2.29 (S, 6H), 1.91-1.86 (m, 1H).

Step-5b Synthesis ofS)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-479)

To a solution of 21.5 (1 g, 17.15 mmol) in DCM (10 mL) was added 4Mhydrochloric acid in 1-4 dioxane (4 mL) at RT. After stirring at 50° C.for 2 h, the reaction mixture was evaporated in vacuum and pH adjust toneutral using NaHCO₃ solution. The aqueous layer was extracted by 15%MeOH/DCM. The organic extracts were evaporated under reduced pressureand the residue triturated with diethyl ether to afford I-479 (500 mg,60.29%) as light yellow solid. MS (ES): m/z 486.55. [M+1]⁺. 1H NMR (400MHz, DMSO-d6) δ 10.05 (S, 1H), 8.85 (S, 1H), 8.78-8.76 (d, J=8.8 Hz,1H), 8.47-8.44 (t, J=13.2 Hz, 1H), 7.83 (S, 1H), 7.74-7.65 (dd, J=28 Hz2H), 7.55-7.52 (dd, J=12 Hz, 1H), 6.99-6.93 (m, 2H), 4.39 (S, 2H),4.01-3.94 (m, 2H), 3.85-3.78 (m, 2H), 3.67-3.64 (m, 1H), 3.55-3.50 (m,2H), 2.33-2.26 (m, 1H) 2.22 (S, 6H), 1.93-1.84 (m, 1H).

Example 22. Method Up Synthesis ofS)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one,(I-707), and(R)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one,(I-708)

Step-1 Synthesis of compound tert-butyl4-chloro-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(22.1)

To a solution of tert-butyl7-bromo-4-chloro-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(17.2) (48 g, 138 mmol) in toluene (480 mL) were added IntermediateAA145 (30.57 g, 138 mmol) and potassium carbonate (57.26 g, 414 mmol,3.0 eq). After degassing with nitrogen for 20 min,4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.99 g, 13.8 mmol, 0.1eq) and tris(dibenzylideneacetone)dipalladium(O) (6.33 g, 6 mmol, 0.05eq) were added. After stirring at 90° C. for 2 h, the reaction wascooled to RT, filtered through celite bed and washed with ethyl acetate(500 mL). The organic layer was washed with water (500 mL), dried overNa₂SO₄, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography eluting with 1.5% to 2.1% MeOH/DCMto afford 22.1 (24 g, 36.03%) as orange solid. MS (ES): m/z 487.52[M+1]⁺¹H NMR (400 MHz, DMSO-d6) δ 9.81 (S, 1H), 9.15 (s, 1H), 7.70 (d,J=8 Hz, 1H), 7.13 (d, J=8 Hz, 1H), 4.75 (s, 2H), 4.01-3.94 (m, 2H),3.84-3.77 (m, 2H), 3.62 (d, J=12.1 Hz, 1H), 3.54-3.48 (m, 2H), 2.33-2.28(m, 1H), 2.20 (s, 6H), 1.94-1.87 (m, 1H), 1.55 (s, 9H).

Step-2 Synthesis of compound tert-butyl7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(22.2)

To a solution of 22.1 (24 g, 49.0 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(19.4 g, 74 mmol, 1.5 eq) in 1-4 dioxane (192 mL), water (48 mL) wasadded potassium phosphate tribasic (31.40 g, 148 mmol, 3.0 eq). Afterdegassing with nitrogen for 20 min, XPhos pdG2 (3.88 g, 4.9 mmol, 0.1eq) was added. After stirring at 100° C. for 3 h, the reaction wascooled to RT, filtered through celite bed and celite bed washed by ethylacetate (250 mL). The organic layer was collected and concentrated underreduced pressure. The residue was purified by silica gel chromatographyeluting with 2.0% to 3.5% MeOH/DCM. The product was then triturated withhexane to afford 22.2 (21 g, 73%) as light yellow solid. MS (ES): m/z587.20 [M+1]⁺

Step-3 Chiral Separation

22.2 (22 g racemic) was separated on Shimadzu LC-20AP and UV detectorusing Chiralcel OX-H (250*21.0) mm, 5 micron, at 20.0 mL/min with mobilephase were (A) 0.1% Diethylamine in n-Hexane (B) 0.1% diethylamine inpropane-2-ol: acetonitrile (70:30) to afford 22.3 (8.5 g) and 22.4 (7g). Stereochemistry arbitrary assign.

¹H NMR (400 MHz, DMSO-d6)_Isomer-1-(22.3): δ 10.17 (S, 1H), 9.46 (s,1H), 8.39 (d, J=8 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.60 (s, 1H), 7.35 (d,J=8 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 6.82 (d, J=6 Hz, 1H), 4.96 (s, 2H),4.03-3.96 (m, 2H), 3.89 (s, 3H), 3.84-3.80 (m, 2H), 3.65 (d, 1H), 3.56(t, 1H), 2.34-2.30 (m, 1H), 2.23 (s, 6H), 1.94-1.89 (m, 1H), 1.55 (s,9H).

¹H NMR (400 MHz, DMSO-d6)_Isomer-2 (22.4): δ 10.16 (S, 1H), 9.46 (s,1H), 8.40 (d, J=8 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.61 (s, 1H), 7.37 (d,J=8 Hz, 1H), 7.14 (d, J=8 Hz, 1H), 6.80 (d, J=6 Hz, 1H), 4.98 (s, 2H),4.02-3.96 (m, 2H), 3.89 (s, 3H), 3.85-3.79 (m, 2H), 3.65 (d, 1H), 3.56(t, 1H), 2.34-2.30 (m, 1H), 2.23 (s, 6H), 1.93-1.90 (m, 1H), 1.56 (s,9H).

Step-4a Synthesis ofS)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one,(I-707)

To a solution of 22.3 (8.5 g, 17.56 mmol) in DCM (90 mL) was added 4Mhydrochloric acid in 1,4 dioxane (50 mL) at RT. After stirring at 55° C.for 2 h, the reaction mixture was evaporated in vacuum. The crudeproduct was poured in to sat NaHCO₃ solution and extracted with 15%MeOH/DCM. The organic layer was separated, dried with Na₂SO₄, andconcentrated under reduced pressure and triturated with diethyl ether toafford I-707 (5.7 g, 81%) MS (ES): m/z 487 [M+H]⁺. 1H NMR (400 MHz,DMSO-d6) δ 10.12 (S, 1H), 9.7 (s, 1H), 9.22 (S, 1H), 8.36-8.35 (d, J=4Hz, 1H), 7.70-7.68 (d, J=8 Hz, 1H), 7.59-7.58 (d, J=3.6 Hz, 1H),7.39-7.38 (d, J=5.2 Hz, 1H), 7.04-7.02 (d, J=8.4 Hz, 1H), 6.90-6.89 (d,J=3.6 Hz, 1H), 4.70 (s, 2H), 4.02-3.99 (m, 2H), 3.85-3.84 (d, J=2 Hz,2H), 3.81-3.79 (m, 2H), 3.65 (S, J=1H, 2H), 2.52-2.51 (t, J=3.6 Hz, 2H),2.23 (s, 5H), 1.93-1.88 (m, 1H).

Step-4b Synthesis ofR)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one,(I-708)

To a solution of 22.4 (1 g, 17.12 mmol) in DCM (10 mL) was added 4Mhydrochloric acid in 1-4 dioxane (4 mL) at RT. After stirring at 55° C.for 2 h, the reaction mixture was evaporated in vacuum. The crudeproduct was poured in to sat NaHCO₃ solution and extracted with 15%MeOH/DCM. The organic layer was separated, dried with Na₂SO₄, andconcentrated under reduced pressure and triturated with diethyl ether toafford I-708 (550 mg, 66.39%) MS (ES): m/z 487 [M+H]⁺. 1H NMR (400 MHz,DMSO-d6) δ 10.11 (S, 1H), 9.69 (s, 1H), 9.22 (S, 1H), 8.36-8.35 (d,J=4.4 Hz, 1H), 7.70-7.68 (d, J=8 Hz, 2H), 7.59 (S, 1H), 7.39-7.38 (d,J=4.4 Hz, 2H), 7.05-7.03 (d, J=8 Hz, 1H), 6.88 (S, 1H), 4.70 (s, 2H),4.00-3.98 (d, J=8 Hz, 2H), 3.87 (S, 3H), 3.84-3.80 (s, J=16 Hz, 2H),3.67 (S, 1H), 3.55-3.51 (m, 2H), 2.24 (s, 6H), 1.92-1.91 (d, J=6.8 Hz,1H).

Example 23. Method Vp Synthesis of4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-46-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-5-((R)-tetrahydrofuran-3-yl)pyridin-2-yl)amino)isoindolin-1-one(I-778) and4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((6-4(S)-3-hydroxypyrrolidin-1-yl)methyl)-5-((S)-tetrahydrofuran-3-yl)pyridin-2-yl)amino)isoindolin-1-one(I-779)

Step-1 Synthesis of(6-amino-3-(tetrahydrofuran-3-yl)pyridin-2-yl)methanol (23.1)

To a solution of Intermediate-AA145-6 (1.0 g, 5.15 mmol) in DCM (5.0 L)at 0° C. was added TFA (2.1 L). After stirring at 70° C. for 2 h, thereaction mixture was evaporated, diluted in water (2 L), and extractedwith heptane. The aqueous layer was neutralized with 10% NaOH solutionand extracted by 15% MeOH in DCM (4×3 L). The combined organic layer wasdried over sodium sulfate and concentrated under reduced pressure. Theresidue was triturated with 20% ethyl acetate in hexanes and thendiethyl ether to afford 23.1 as light brown solid. (330 g, 68.47%). MS(ES): m/z 222.30 [M+1]⁺, 1H NMR (400 MHz, DMSO-d6) δ 7.33 (d, J=8.4 Hz,1H), 6.36 (d, J=8.5 Hz, 1H), 5.71 (s, 1H), 3.96-3.85 (m, 1H), 3.72 (dq,J=31.0, 7.7 Hz, 1H), 3.46-3.34 (m, 1H), 3.35 (s, 1H), 3.30 (d, J=11.9Hz, 0H), 2.19 (td, J=7.8, 4.2 Hz, 0H), 2.14 (s, 3H), 1.79 (dq, J=12.2,8.0 Hz, 1H).

Step-2 Synthesis of tert-butyl4-chloro-7-((6-(hydroxymethyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(23.2)

tert-butyl4-chloro-7-((6-(hydroxymethyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate23.2 was prepared from tert-butyl(6-(hydroxymethyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)carbamate (23.1)in a similar fashion to that described in tert-butyl4-chloro-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(21.1) (0.930 g, 41.3%) m/z 460.16 [M+H]⁺

Step-3 Synthesis of tert-butyl(S)-7-((6-(hydroxymethyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-1-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate(23.3)

tert-butyl(S)-7-((6-(hydroxymethyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-1-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate(23.3) was synthesize from tert-butyl4-chloro-7-((6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(23.2) in a similar fashion to that described in tert-butyl7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-1-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate(19.2) (0.700 g, 62.7%), m/z 552.4 [M+H]⁺

Step-4 Synthesis of tert-butyl(S)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((6-(hydroxymethyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(23.4)

tert-butyl(S)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-746-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(23.4) was synthesize from tert-butyl(S)-7-((6-(hydroxymethyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-1-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate(23.3) in a similar fashion to that described in tert-butyl7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate(21.3) (0.4 g, 56.3%). m/z 559.6 [M+H]⁺.

Step-5 & Step-6 Synthesis of tert-butyl(S)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((6-(((methylsulfonyl)oxy)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(23.6)

tert-butyl(S)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-′746-(((methylsulfonyl)oxy)methyl)-5-(THF-3-yl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(23.6) was synthesize from 23.4 & 23.5 in a similar fashion to thatdescribed in (step-2, 3) tert-butyl(R)-(6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)carbamate(20.2). (0.170 g, 37.8%). m/z 628.7 [M+H]⁺.

Step-7 Chiral Separation

23.6 (0.17 gm) was separated on Shimadzu LC-20AP and UV detector usingCHIRALPAK IC (250*21.0) mm, 5 micron, at 20.0 mL/min with mobile phase(A) 0.1% DEA IN n-Hexane, (B) 0.1% DEA in propane-2-ol:acetonitrile(70:30) to afford 23.6a (58 mg) and 23.6b (65 mg). Stereochemistryarbitrary assign

Step-8a Synthesis of4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-46-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-5-((R)-tetrahydrofuran-3-yl)pyridin-2-yl)amino)isoindolin-1-one(I-778)

4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((6-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-5-((R)-tetrahydrofuran-3-yl)pyridin-2-yl)amino)isoindolin-1-one(I-778) was synthesize from 23.6a in a similar fashion to that describedin step-5a(R)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-478) in Example 21.

(30 mg, 61.52%). MS (ES): m/z 529 [M+1]⁺, ¹H NMR (400 MHz, DMSO-d6) δ10.05 (s, 1H), 8.83-8.80 (d, J=4 Hz 2H), 8.46-8.43 (t, J=6.7 Hz, 1H),7.83 (s, 1H), 7.69 (dd, J=33.0, 8.5 Hz, 1H), 7.54-7.51 (dd, J=10.1, 2.6Hz, 2H), 7.02-6.89 (m, 2H), 4.65 (d, J=4.2 Hz, 1H), 4.39 (s, 1H), 4.19(tt, J=7.7, 3.8 Hz, 2H), 4.05-3.87 (m, 1H), 3.89-3.71 (m, 2H), 3.67 (d,J=12.1 Hz, 1H), 3.60-3.48 (m, 2H), 3.31 (s, 1H), 2.76 (dd, J=9.7, 6.3Hz, 2H), 2.65 (t, J=7.9 Hz, 1H), 2.50-2.42 (m, 2H), 2.40-2.22 (m, 1H),2.05-1.82 (m, 1H), 1.54 (s, 1H).

Step-8b Synthesis of4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-46-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-5-((S)-tetrahydrofuran-3-yl)pyridin-2-yl)amino)isoindolin-1-one(I-779)

4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((6-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-5-((S)-tetrahydrofuran-3-yl)pyridin-2-yl)amino)isoindolin-1-one(I-779) was synthesize from 23.6b in a similar fashion to that describedin step-5b(S)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-479) in Example 21.

(30 mg, 61.52%). MS (ES): m/z 529 [M+1]⁺, ¹H NMR (400 MHz, DMSO-d6) δ10.05 (s, 1H), 8.83-8.80 (d, J=12 Hz, 2H), 8.47-8.43 (t, J=12 Hz, 1H),7.83 (s, 1H), 7.74-7.71 (d, J=12 Hz, 1H), 7.65-7.63 (d, J=8.5 Hz, 1H),7.53 (dd, J=10.0, 2.7 Hz, 1H), 7.02-6.89 (m, 2H), 4.67 (d, J=4.2 Hz,1H), 4.39 (s, 1H), 4.19 (s, 1H), 4.04-3.90 (m, 2H), 3.83-3.68 (m, 2H),3.60-3.48 (m, 2H), 3.34 (s, 2H), 2.73 (dd, J=9.6, 6.2 Hz, 1H), 2.62 (q,J=7.7 Hz, 1H), 2.48 (s, 1H), 2.39 (dd, J=9.6, 3.8 Hz, 1H), 2.28 (dd,J=12.6, 8.4, 4.9 Hz, 2H), 2.05-1.83 (m, 1H), 1.56-1.44 (m, 1H)

Example 24. Method Wp Synthesis of(S)-7-((6-(aminomethyl)-5-(THF-3-yl)pyridin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-836) and(R)-7-((6-(aminomethyl)-5-(THF-3-yl)pyridin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-829)

Step-1 Synthesis of tert-butyl4-chloro-7-((6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)amino)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(24.1)

tert-butyl4-chloro-7-((6-(hydroxymethyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(24.1) was prepared from tert-butyl(6-(hydroxymethyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)carbamate (23.1)and tert-butyl7-bromo-4-chloro-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(17.2) in a similar fashion to that described in tert-butyl4-chloro-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(21.1) (10 g, 35%). m/z 460.15 [M+H]⁺.

Step-2 Synthesis of tert-butyl(S)-7-((6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(24.2)

tert-butyl(S)-7-((6-(hydroxymethyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-441-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(24.2) was prepared from tert-butyl4-chloro-7-((6-(hydroxymethyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate24.1 and Intermediate BB14 in a similar fashion to that described instep-2 tert-butyl7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(22.2). (3.5 g, 72.21%). m/z 557.24 [M+H]⁺.

Step 3 to Step 6a, 6b were carried out following representativeprocedures described in Example 22 to afford I-829 and I-836.

I-829 (35 mg) m/z=456.0 [M+H]+¹H NMR (400 MHz, DMSO): δ 9.92 (s, 1H),9.77 (s, 1H), 9.30 (s, 1H), 8.46 (bs, 3H), 8.40-8.39 (d, J=4.8 Hz, 1H),7.77-7.75 (d, J=8.4 Hz, 1H), 7.44-7.43 (d, J=4.8 Hz, 1H), 7.18-7.16 (d,J=8.8 Hz, 1H), 6.97-6.96 (d, J=3.6 Hz, 1H), 4.75 (bs, 2H), 4.36-4.35 (d,J=5.2 Hz, 2H), 3.99-3.95 (m, 3H), 3.86 (s, 4H), 3.44-3.40 (m, 2H),2.37-2.34 (m, 1H).

I-836 (9 mg) m/z=456.0 [M+H]+¹H NMR (400 MHz, DMSO): δ 10.09 (bs, 1H),9.67 (bs, 2H), 9.23 (bs, 1H), 8.36-8.35 (d, J=5.2 Hz, 1H), 7.66-7.56 (m,2H), 7.40-7.37 (t, J=5.2 Hz, 1H), 6.99 (s, 1H), 6.91-6.90 (d, J=2.8 Hz,2H), 4.72 (bs, 2H), 4.34 (bs, 1H), 3.95-3.87 (m, 3H), 3.82 (s, 4H),3.64-3.57 (m, 2H), 2.33-2.29 (m, 1H), 1.87 (bs, 1H).

Example 25. Method Xp Synthesis of7-46-((dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-792)

Step-1 Synthesis of tert-butyl4-chloro-7-((6-((dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(25.1)

To a solution of 3.5 (75 g, 216.7 mmol) in 1-4 dioxane (750 mL) wereadded Intermediate AA191 (51.14 g, 216.7 mmol) and cesium carbonate(211.28 g, 650.1 mmol, 3.0 eq). After degassing with nitrogen for 20min, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (25.09 g, 43.34mmol, 0.2 eq) and tris(dibenzylideneacetone)dipalladium(O) (19.82 g,21.67 mmol, 0.1 eq) were added. After stirring at 90° C. for 2 h, thereaction was cool to RT, filtered through celite bed and the celite bedwas washed with ethyl acetate (2.5 L). The combined organic layer waswashed with water (2 L), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by silica gelchromatography eluting with 1-6% methanol/DCM to afford 25.1. (60 g,56%) as orange solid. MS (ES): m/z 502.02 [M+1]⁺

Step-2 Synthesis of tert-butyl7-((6-((dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)-1-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate(25.2)

To a solution of the 25.1 (60 g, 119.0 mmol) in 1-4 dioxane (600 mL),were added bis(pinacolato)diboron (60.50 g, 239.0 mmol, 2.0 eq) andpotassium acetate (35.01 g, 357.0 mmol, 3.0 eq). After degassing withnitrogen for 20 min, XPhos Pd G2 (9.36 g, 11.9 mmol, 0.1 eq) was added.After stirring at 90° C. for 2 h, the reaction was cool to RT, filteredthrough celite and the celite bed was washed with ethyl acetate (1.5 L).The combined organic layer was washed with water (1 L), dried overNa₂SO₄, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography to afford 25.2. (43 g, 60%) asbrown solid. MS (ES): m/z 593.54 [M+H]⁺.

Step-3 Synthesis of tert-butyl7-((6-((dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate(25.3)

To a solution of the 25.2 (45 g, 76.01 mmol) in 1-4 dioxane (360 mL) andwater (90 mL) were added 7-fluoro-3-iodoimidazo[1,2-a]pyridine(Intermediate BB63) (24.47 g, 91.21 mmol, 1.2 eq) and potassiumphosphate tribasic (48.33 g, 2.0 mmol, 3.0 eq). After degassing withnitrogen for 20 min, XPhos pdG2 (5.97 g, 7.6 mmol, 0.1 eq) and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (1.85 g, 3.8 mmol,0.05 eq) were added. After stirring at 100° C. for 3 h, the reaction wascooled to RT, filtered through celite bed and the celite bed washed withethyl acetate (1 L). The combined organic layer washed with water (1.5L) and concentrated under reduced pressure. The residue was purified bysilica gel chromatography eluting with 2-5% methanol in DCM to afford25.3. (21 g, 48.17%). MS (ES): m/z 601.29 [M+1]⁺.

Step-4 Synthesis of7-46-((dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-792)

To a solution of 25.3 (21 g, 34.92 mmol) in DCM (210 mL) was added 4Mhydrochloric acid in 1,4 dioxane (84 mL) at RT. After stirring at 50° C.for 2 h, the reaction mixture was evaporated in vacuum and pH adjustedto neutral using NaHCO₃ solution. The aqueous layer was extracted by 15%MeOH/DCM. The organic solution was evaporated under reduced pressure andthe residue triturated with diethyl ether to afford I-792. (10 g,57.14%). MS (ES): m/z 501.55. [M+1]⁺. ¹H NMR (400 MHz, DMSO): δ 10.03(s, 1H), 8.83 (s, 1H), 8.78-8.76 (d, J=8 Hz, 1H), 7.47-7.44 (t, J=6.4Hz, 1H), 7.83 (s, 1H), 7.74-7.72 (d, J=8.4 Hz, 1H), 7.68-7.66 (d, J=8Hz, 1H), 7.55-7.52 (dd, J=2.4 Hz, 1H), 6.96-6.94 (t, J=2 Hz, 1H), 6.92(s, 1H), 4.39 (s, 2H), 3.99-3.96 (dq, 2H), 3.59 (s, 2H), 3.47-3.42 (t,J=10.4 Hz, 2H), 3.28 (s, 1H), 3.20 (bs, 1H), 2.24 (s, 6H), 1.70-1.65 (m,3H).

Example 26. Method Yp Synthesis of(R)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-(1-morpholinoethyl)pyridin-2-yl)amino)isoindolin-1-one(I-639) and(S)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-(1-morpholinoethyl)pyridin-2-yl)amino)isoindolin-1-one(I-640)

Step-1 Synthesis of tert-butyl4-chloro-7-((5-(1-morpholinoethyl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(26.1)

To a solution of 3.5 (0.350 g, 1.01 mmol) and Intermediate AA118 (0.252g, 1.21 mmol, 1.2 eq) in 1, 4-dioxane (8 mL) were added potassiumcarbonate (0.278 g, 2.02 mmol, 2.0 eq) and Xantphos (0.058 g, 0.10 mmol,0.1 eq). After degassing under N2 stream for 15 min, Pd₂(dba)₃ (0.046 g,0.05 mmol, 0.05 eq) was added. After stirring at 100° C. and for 1 h,the reaction mixture was cooled to RT, diluted with water (50 mL) andextracted with ethyl acetate (3×30 mL). The combined organic extractswere washed with brine (30 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography 2% methanol gradient in DCM to afford 26.1 (0.250 g,52.34%) as a brown solid. MS (ES): m/z=474.18 [M+2]⁺

Step-2 Synthesis of tert-butyl7-((5-(1-morpholinoethyl)pyridin-2-yl)amino)-1-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate(26.2)

To a solution of 26.1 (0.250 g, 0.52 mmol) in dioxane (6 mL). were addedbis(pinacolato)diboron (0.336 g, 1.32 mmol, 2.5 eq) and potassiumacetate (0.155 g, 1.58 mmol, 3.0 eq). After degassing with N2 for 15min, X-Phos Pd G3 (0.021 g, 0.026 mmol, 0.05 eq) was added. Afterstirring at 100° C. for 1 h, the reaction mixture was cooled to RT,diluted with water (40 mL) and extracted with ethyl acetate (3×20 mL).The combined organic extracts were washed with brine (40 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure to afford 26.2(0.3 g) which was used in the next step without further purification. MS(ES): m/z 565.32 [M+H]⁺

Step-3 Synthesis of tert-butyl4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-(1-morpholinoethyl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(26.3)

To a solution of 26.2 (0.3 g, 0.53 mmol)) in dioxane (3 mL) and water (1mL) were added Intermediate BB63 (0.13 g, 0.63 mmol, 1.2 eq) andpotassium phosphate tribasic (0.337 g, 1.59 mmol, 3.0 eq). Afterdegassing with N2 for 15 min, X-Phos Pd G2 (0.041 g, 0.053 mmol, 0.1 eq)was added. After stirring at 110° C. for 20 min in microwave, thereaction mixture was cooled to RT, diluted with water (40 mL) andextracted with ethyl acetate (3×20 mL). The combined organic extractswere washed with brine (40 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 3.0% methanol gradient in DCM to afford 26.3(0.2 g, 78%), MS (ES): m/z 573.26 [M+H]⁺

Step-4 Synthesis of tert-butyl(R)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-(1-morpholinoethyl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(25.4) and tert-butyl(S)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-(1-morpholinoethyl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(25.5)

26.3 (110 mg) was separated on Shimadzu LC-20AP and UV detector usingCHIRALPAK (250*21.0) mm, 5 micron at 20.0 mL/min with mobile phase (A)0.1% DEA IN n-Hexane and (B)_(0.1)% DEA in propanol:methanol (50:50) toafford 26.4 (45 mg) and 26.5 (44 mg). Stereochemistry was arbitraryassigned.

Step-5a Synthesis ofR)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-(1-morpholinoethyl)pyridin-2-yl)amino)isoindolin-1-one(I-639)

To a solution of tert-butyl(R)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-745-(1-morpholinoethyl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(26.4) (0.045 g, 0.07 mmol) in DCM (1 mL) at 0° C. was added 4M HCl indioxane (0.4 mL). After stirring at RT for 1 h, the reaction mixture wasneutralized using saturated sodium bicarbonate solution and extractedwith 10% methanol in DCM (3×10 mL). The combine organic layer wasconcentrated under reduced pressure. The residue was purified by columnchromatography to afford the title compound I-639 (0.030 g, 80.79%) aswhite solid. MS (ES): m/z 473.23 (M+H). ¹H NMR (400 MHz, DMSO-d6) δ10.10 (s, 1H), 8.87 (s, 1H), 8.74-8.72 (d, J=8.6 Hz, 1H), 8.47-8.43 (m,1H), 8.22-8.21 (d, J=2.3 Hz, 1H), 7.84 (s, 1H), 7.76-7.74 (d, J=8.6 Hz,1H), 7.67-7.65 (dd, J=8.4, 2.4 Hz, 1H), 7.56-7.53 (dd, J=10.1, 2.7 Hz,1H), 7.05-6.99 (m, 2H), 4.41 (s, 2H), 3.58-3.56 (t, J=4.6 Hz, 3H),3.45-3.40 (m, 2H), 2.40 (bs, 1H), 2.34-2.30 (m, 3H), 1.34-1.32 (dd,J=6.8 Hz, 3H).

Step-5b Synthesis ofS)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-(1-morpholinoethyl)pyridin-2-yl)amino)isoindolin-1-one(I-640)

To a solution of tert-butyl(S)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-(1-morpholinoethyl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(26.5) (0.045 g, 0.07 mmol) in DCM (1 mL) at 0° C. was added 4M HCl indioxane (0.4 mL). After stirring at RT for 1 h, the reaction mixture wasneutralized using saturated sodium bicarbonate solution and extractedwith 10% methanol in DCM (3×10 mL). The combine organic layer wasconcentrated under reduced pressure. The residue was purified by columnchromatography to afford the title compound I-640 (0.025 g, 67.33%) asWhite solid. MS (ES): m/z 473.21 (M+H). 1H NMR (400 MHz, DMSO-d6) δ10.10 (s, 1H), 8.87 (s, 1H), 8.74-8.72 (d, J=8.6 Hz, 1H), 8.47-8.43 (m,1H), 8.22-8.21 (d, J=2.3 Hz, 1H), 7.84 (s, 1H), 7.76-7.74 (d, J=8.6 Hz,1H), 7.67-7.65 (dd, J=8.4, 2.4 Hz, 1H), 7.56-7.53 (dd, J=10.1, 2.7 Hz,1H), 7.05-6.99 (m, 2H), 4.41 (s, 2H), 3.58-3.56 (t, J=4.6 Hz, 3H),3.45-3.40 (m, 2H), 2.40 (bs, 1H), 2.34-2.30 (m, 3H), 1.34-1.32 (dd,J=6.8 Hz, 3H).

Example 27. Method Zp Synthesis of7-((6-((3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)pyrazin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-660) and7-((6-((3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)pyrazin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-661)

Step-1 Synthesis of tert-butyl7-((6-(5-(tert-butoxycarbonyl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)pyrazin-2-yl)amino)-4-chloro-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(27.1)

A solution of Intermediate AA124 (0.6 g, 1.72 mmol) and 14.2 (0.527 g,1.72 mmol) in 1,4-dioxane (8 mL) was added K₂CO₃ (0.71 g, 5.16 mmol, 3.0eq). After degassing under N2 stream for 15 min, Xantphos (0.2 g, 0.34mmol, 0.2 eq) and Pd₂(dba)₃ (0.157 g, 0.17 mmol, 0.1 eq) were added.After stirring at 110° C. for 5 h, the reaction mixture was cooled toRT, diluted water (50 mL) and extracted with ethyl acetate (3×20 mL).The combined organic extracts were washed with brine (50 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography eluting with 50% ethyl acetategradient in hexane to afford 27.1 (0.5 g, 50.63%) as a brown solid. MS(ES): m/z=573.2 [M+H]⁺

Step-2 Synthesis of tert-butyl7-((6-(5-(tert-butoxycarbonyl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)pyrazin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(27.2)

To a solution of 27.1 (0.490 g, 0.85 mmol) and Intermediate BB14 (0.442g, 1.71 mmol, 2.0 eq) in 1,4-dioxane:water (5 mL: 1 mL) was addedpotassium phosphate tribasic (0.540 g, 2.55 mmol, 3.0 eq). Afterdegassing with N2 for 15 min, X-Phos Pd G2 (0.066 g, 0.085 mmol, 0.1 eq)was added. After stirring at 110° C. for 20 min in microwave, thereaction mixture was cooled to RT, diluted water (60 mL) and extractedwith ethyl acetate (3×30 mL). The combined organic extracts were washedwith brine (70 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with 2% methanol gradient in DCM to afford 27.2 (0.360 g,62.94%), MS (ES): m/z 668.3 [M+H]⁺

Step-3 Separation of tert-butyl7-((6-((3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)pyrazin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(27.3) and tert-butyl7-((6-((3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)pyrazin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(27.4)

27.2 (360 mg) was separated by Chiral SFC in Shimadzu LC-20AP and UVdetector using CHIRALPAK IH (250*4.6 mm) 5u 5 micron at 20 mL/min withmobile phase (A) 0.1% DEA IN n-Hexane and (B) 0.1% DEA inpropanol:acetonitrile (70:30) to afford 27.3 (140 mg) and 27.4 (130 mg).Stereochemistry was arbitrary assigned.

Step-4 Synthesis of7-((6-((3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)pyrazin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-660)

To solution of tert-butyl7-((6-((3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)pyrazin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(27.3) (0.140 g, 0.246 mmol,1.0 eq) into DCM (2 mL) at 0° C. was addeddropwise TFA (0.5 mL). After stirring at RT for 30 min, the reactionmixture was neutralized using saturated sodium bicarbonate solution andextracted with 10% methanol in DCM (3×20 mL). The combine organic layerwas concentrated under reduced pressure. The residue was purified bypreparative HPLC to afford the title compound (I-660) (0.030 g, 26.02%)as off white solid. MS (ES): m/z 468.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6)δ 9.95 (s, 1H), 9.74 (s, 1H), 9.29 (s, 1H), 8.37 (d, J=5.0 Hz, 1H), 8.28(s, 1H), 7.67 (s, 1H), 7.62-7.50 (m, 2H), 7.41 (d, J=5.0 Hz, 1H), 6.88(d, J=3.3 Hz, 1H), 4.72 (s, 2H), 4.48 (bs, 1H), 3.88 (s, 3H), 3.69 (d,J=3.5 Hz, 1H), 3.21 (s, 1H), 3.19 (d, J=6.0 Hz, 2H), 3.16-3.05 (m, 2H),2.88 (dd, J=10.7, 3.1 Hz, 1H), 2.18-2.13 (dq, J=14.6, 7.4 Hz, 1H),1.94-1.90 (dt, J=11.6, 6.2 Hz, 1H).

Step-5 Synthesis of7-((6-((3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)pyrazin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-661)

To solution of tert-butyl7-((6-((3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)pyrazin-2-yl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(27.4) (0.130 g, 0.19 mmol,1.0 eq) into DCM (2 mL) at 0° C. was addeddropwise TFA (0.5 mL). After stirring at RT for 30 min, the reactionmixture was neutralized using saturated sodium bicarbonate solution andextracted with 10% methanol in DCM (3×20 mL). The combine organic layerwas concentrated under reduced pressure. The residue was purified bypreparative HPLC to afford the title compound (I-661) (0.025 g, 23.25%)as off white solid. MS (ES): m/z 468.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6)δ 9.96 (s, 1H), 9.74 (s, 1H), 9.29 (s, 1H), 8.37 (d, J=4.9 Hz, 1H), 8.28(s, 1H), 7.67 (s, 1H), 7.60 (d, J=3.5 Hz, 1H), 7.55 (s, 1H), 7.41 (d,J=4.9 Hz, 1H), 6.88 (d, J=3.4 Hz, 1H), 4.73 (s, 2H), 4.47 (s, 1H), 3.89(s, 3H), 3.69-3.66 (m, 1H), 3.58 (d, J=8.6 Hz, 1H), 3.18 (s, 1H), 3.09(d, J=12.0 Hz, 2H), 3.02 (d, J=11.5 Hz, 2H), 2.86 (d, J=9.6 Hz, 1H),2.16 (dd, J=12.9, 6.9 Hz, 1H).

Example 28. Method AAp Synthesis of7-((6-((dimethylamino)methyl)-5-(3-(methoxymethyl)THF-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-837)

Step-1 Synthesis of 3-bromo-2-methylbenzoic acid (28.2)

To a solution of 28.1 (1 g, 4.3 mmol) in methanol (10 mL) was added NaOH(873 mg, 21.82 mmol, 5 eq). After stirring at 60° C. for 1 h, thereaction mixture was quenched with dilute HCl (100 mL) and extractedwith ethyl acetate (100 mL×3). The combined organic layer was dried oversodium sulfate and concentrated under reduced pressure. The residue waspurified by column chromatography using neutral alumina eluting with5-10% methanol in DCM to afford 28.2 (730 mg, 77%). MS (ES): m/z 216.05[M+2]⁺.

Step-2 Synthesis of 3-bromo-6-chloro-2-methylbenzoic acid (28.3)

To a solution of 27.2 (9.3 g, 43.2 mmol) in DMF (90 mL) were added NCS(6.93 g, 51.9 mmol, 1.2 eq) and Pd(OAc)₂ (4.85 g, 224.5 mmol, 0.5 eq).After stirring at 110° C. for 16 h., the reaction was diluted with water(1.5 L) and extracted by ethyl acetate (2×2 L). The combined organiclayer dried over sodium sulfate, filtered, and concentrated undervacuum. The residue was purified by column chromatography to afford 28.3(9 g, 83.41%). MS (ES): m/z 247.92 [M+2]⁺.

Step-3 Synthesis of methyl 3-bromo-6-chloro-2-methylbenzoate (28.4)

To a solution of 28.3 (9 g, 36.07 mmol) in DMF (90 mL) was added K₂CO₃(12.4 g, 90.18 mmol, 2.5 eq). After stirring at RT for 30 min, methyliodide (5.6 g, 39.68 mmol, 1.1 eq) was added. After stirring for 16 hrat RT, the reaction was diluted with dilute HCl (300 mL) and extractedby ethyl acetate (3×500 mL). The combined organic layer dried oversodium sulfate and dried under vacuum. The residue was purified bycolumn chromatography to afford 28.4 (8 g, 84.16%). MS (ES): m/z 264.52[M+2]⁺.

Step-4 Synthesis of methyl 3-bromo-2-(bromomethyl)-6-chlorobenzoate(28.5)

To a solution of 28.4 (8 g, 30.36 mmol) in CCl₄ (80 mL) were added NBS(5.9 g, 33.39 mmol, 1.1 eq) and DBPO (14.7 mg, 0.06 mmol, 0.002 eq).After stirring at 110° C. for 16 h, the reaction was diluted with water(300 mL) and extracted by ethyl acetate (3×500 mL). The combined organiclayer dried over sodium sulfate, filtered, and concentrated under vacuumto afford crude which was purified by Colum chromatography to afford28.5 (8 g, 76.96%). MS (ES): m/z 342.41 [M+2]⁺.

Step-5 Synthesis of 4-bromo-7-chloroisoindolin-1-one (Intermediate 28.6)

To a solution of 28.5 (9.5 g, 27.7 mmol) in methanol (95 mL), ammoniagas was purged for 16 hr at RT. After completion of reaction, thereaction was diluted with water (300 mL) and extracted by ethyl acetate(3×500 mL). The combined organic layer dried over sodium sulfate anddried under vacuum. The residue was purified by trituration with diethylether to afford 28.6 (4 g, 61.74%). MS (ES): m/z 247.69 [M+2]⁺.

Step-6 tert-butyl 4-bromo-7-chloro-1-oxoisoindoline-2-carboxylate (28.7)

To a solution of 28.6 (3.8 g, 15.41 mmol) in THF (45 mL) were added(BOC)₂O (5.04 g, 23.12 mmol, 1.5 eq) and DMAP (2.3 g, 18.49 mmol, 1.2eq). After stirring at RT for 4 h, the reaction was diluted with water(150 mL) and extracted by ethyl acetate (3×100 mL). The combined organiclayer dried over sodium sulfate and concentrated under vacuum. Thereside was purified by column chromatography to afford 28.7 (3.8 g,80.51%). MS (ES): m/z 345.61 [M+2]⁺.

Step-7 Synthesis of tert-butyl7-chloro-1-oxo-4-(trimethylstannyl)isoindoline-2-carboxylate(Intermediate 28.8)

To a solution of 28.7 (900 mg, 2.6 mmol) in toluene (9 mL) was addedhexamethylditin (1.2 g, 3.9 mmol, 1.5 eq). After degassing with flow ofnitrogen for 20 min, bis(triphenylphosphine)palladium(II) dichloride(182 mg, 0.026 mmol, 0.1 eq) was added. After stirring at 110° C. for 2h, the reaction was cool to RT, diluted with water (150 mL) andextracted with EtOAc (3×60 mL). The combined organic extract was driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by silica gel chromatography to afford 28.8 (480 mg, 55.71%).MS (ES): m/z 401.09 [M+1]⁺

Step-8 Synthesis of tert-butyl7-chloro-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate(28.9)

To a solution of 28.8 (900 mg, 76.01 mmol) in 1-4 dioxane (9 mL) wasadded 3-bromo-7-fluoroimidazo[1,2-a]pyridine (658 mg, 2.5 mmol, 1.2 eq).After degassing with flow of nitrogen for 20 min, CuI (39 mg, 0.2 mmol,0.1 eq) and tetrakis(triphenylphosphine)-palladium(O) (237 mg, 0.20mmol, 0.1 eq) were added. After stirring at 100° C. for 1 h, thereaction was cool to RT, diluted with water (150 mL) and extracted withEtOAc (3×60 mL). The combined organic extract was dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to afford 28.9 (480 mg, 23%). MS (ES): m/z 401.09[M+1]⁺

Step-1 Synthesis of tert-butyl7-((6-((dimethylamino)methyl)-5-(3-(methoxymethyl)tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate(28.10)

To a solution of 28.9 (290 mg, 0.7 mmol, 1.2 eq) in 1-4 dioxane (750 mL)were added Intermediate AA212 (160 mg, 0.6 mmol) and cesium carbonate(590 mg, 1.8 mmol, 3.0 eq) at RT. After degassing with flow of nitrogenfor 20 min, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (70 mg, 0.12mmol, 0.2 eq) and tris(dibenzylideneacetone)dipalladium(O) (55 g, 0.06mmol, 0.1 eq) were added. After stirring at 90° C. for 2 h, the reactionwas cool to RT, diluted with water (20 mL) and extracted with EtOAc(3×20 mL). The combined organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to afford 27.10 (170 mg, 67%). MS (ES): m/z 631.2[M+1]⁺

Step-2 Synthesis of7-((6-((dimethylamino)methyl)-5-(3-(methoxymethyl)tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-837)

To a solution of 28.10 (120 mg, 0.2 mmol) in DCM (5 mL) was added 4Mhydrochloric acid in 1-4 dioxane (2 mL) at RT. After stirring at RT for2 h, the reaction mixture was evaporated in vacuum, the pH wasneutralized using NaHCO₃ solution and extracted by 15% MeOH/DCM. Theorganic extract was evaporated under reduced pressure and triturated bydiethyl ether to afford I-837 (30 mg, 30%). MS (ES): m/z 531.34 [M+1]⁺.¹H NMR (400 MHz, DMSO): δ 10.05 (s, 1H), 8.85 (bs, 2H), 8.46-8.42 (d,J=6 Hz, 1H), 7.95 (s, 1H), 7.74-7.72 (d, J=8.8 Hz, 1H), 7.55-7.54 (d,J=2.4 Hz, 1H), 7.45-7.43 (d, J=8.4 Hz, 1H), 6.99-6.97 (t, J=2.4 Hz 1H),6.81 (s, 1H), 4.39 (s, 2H), 4.26-4.23 (d, J=8.4 Hz, 1H), 3.94-3.88 (m,2H), 3.53-3.47 (m, 3H), 3.14 (s, 3H), 2.37 (s, 3H), 2.27 (s, 6H), 1.23(s, 1H).

Example 29. Method ABp Synthesis of(R)-7-((6-((dimethylamino)methyl)-5-(6-hydroxy-1,4-oxazepan-4-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-819) and(S)-7-((6-((dimethylamino)methyl)-5-(6-hydroxy-1,4-oxazepan-4-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-820)

Step-1 synthesis of tert-butyl7-amino-4-chloro-1-oxoisoindoline-2-carboxylate (29.1)

To a solution of tert-butyl4-chloro-7-nitro-1-oxoisoindoline-2-carboxylate (14.1) (170 g, 0.801mol) in ethyl acetate (1360 mL) at 0° C. were added acetic acid (340 mL)dropwise and zinc (367 g, 5.61 mol) portion wise. After stirringovernight, the reaction mixture was cooled, neutralized with sodiumbicarbonate solution, filtered through celite bed, and extracted withethyl acetate (3×1 L). The combined organic extracts were washed withbrine (1.2 L), dried over Na₂SO₄, filtered, and concentrated underreduced pressure to afford 29.1 (135 g, 88.13%), MS (ES): m/z=282.6[M+H]⁺

Step-2 synthesis of7-amino-2-(tert-butoxycarbonyl)-1-oxoisoindolin-4-yl)boronic acid (29.2)

To a solution of 29.1 (7 g, 24.8 mmol) in ethanol (10 mL) were addedtetrahydroxy diborane (8.83 g, 99.0 mmol, 4 eq), ethylene glycol (4.46g, 72.2 mmol, 3 eq) and potassium acetate (7.05 g, 72.1 mmol, 3 eq).After degassing with argon for 10 min, X-Phos Pd G2 (943 mg, 1.2 mmol,0.05 eq) and X-Phos (571 mg, 1.2 mmol, 0.05 eq) were added. Afterstirring at 80° C. for 1 h, the reaction mixture was poured into waterand extracted with EtOAc (30 mL×3). The combined organic layer waswashed with brine solution, dried over sodium sulfate, and concentratedunder reduced pressure. The residue was purified by trituration withEther: pentane (1:1) to afford 29.2 (5.4 g, 77.5%). MS (ES): m/z 293.1(M+H)⁺.

Step-3 synthesis of tert-butyl7-amino-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate(29.3)

To a solution of 29.2 (5.4 g, 18.4 mmol) in dioxane:H₂O (50:10 mL) wereadded 7-fluoro-3-iodoimidazo[1,2-a]pyridine (5.81 g, 22.0 mmol) andpotassium phosphate tribasic (11.7 g, 55.2 mmol, 3.0 eq). Afterdegassing using N2 for 15 min, X-Phos Pd G2 (1.44 g, 1.84 mmol, 0.1 eq)was added. After stirring at 100° C. for 1 h, the reaction mixture waspoured into water and extracted with EtOAc (50 mL×3). The combinedorganic layer was washed with brine solution, dried over sodium sulfate,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 0-100% gradient elution EtOAc inhexane to afford 29.3. (4.5 g, 63.3%). MS (ES): m/z 383.3 (M+H)⁺.

Step-1 Synthesis of tert-butyl7-((5-(6-(benzyloxy)-1,4-oxazepan-4-yl)-6-((dimethylamino)methyl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate(29.4)

To a solution of tert-butyl7-amino-4-(7-fluoroimidazo[1,2-a]pyridine-3-yl)-1-oxoisoindoline-2-carboxylate(29.3) (0.300 g, 0.799 mmol) in 1,4-dioxane (5 mL) were added1-(3-(6-(benzyloxy)-1,4-oxazepan-4-yl)-6-chloropyridine-2-yl)-N,N-dimethylmethanamine(Intermediate-AA202) (0.225 g, 0.588 mmol, 0.75 eq) and potassiumcarbonate (0.275 g, 1.99 mmol). After stirring at RT for 5 min underargon, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.2 eq) andtris(dibenzylideneacetone)dipalladium (0.1 eq) were added. Afterstirring at 110° C. temperature for 1.5 h, the reaction mixture wascooled at RT, diluted with water (200 mL), and extracted with ethylacetate (3×200 mL). The combined organic extracts were washed with brine(100 mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography (3% methanolgradient in DCM) to afford 29.4 (0.330 g, 58.30%), MS (ES): m/z=721.2[M+H]⁺

Step-2 Synthesis of7-((6-((dimethylamino)methyl)-5-(6-hydroxy-1,4-oxazepan-4-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(29.5)

To a solution of 29.4 (300 mg, 0.416 mmol) in DCM (10 mL) at 0° C. wasadded triflic acid (1 mL). After stirring for 10 min, the reactionmixture was neutralized with 1N sodium hydroxide solution and extractedwith DCM. The combined organic layer was dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified bytrituration with diethyl ether to afford 29.5 as racemic mixture (123mg, Yield: 75.34%).

Step-3 Chiral separation:(R)-7-((6-((dimethylamino)methyl)-5-(6-hydroxy-1,4-oxazepan-4-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-819) and(S)-7-((6-((dimethylamino)methyl)-5-(6-hydroxy-1,4-oxazepan-4-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-820)

29.5 (123 mg) was separated by Chiral compound using Shimadzu LC-20APand UV detector with CHIRALPAK IC (250*21.0) mm, 5 micron, at 18.0mL/min with mobile phase (A) 0.1% DEA IN n-Hexane and (B) 0.1% DEA inpropane-2-ol:acetonitrile (70:30) to afford compounds I-819 (17.5 mg)and I-820 (12 mg). Stereochemistry was arbitrary assigned.

I-819: MS (ES): m/z=532.2 [M+1-1]+, 1H NMR (400 MHz, DMSO-d6)Isomer-1-(I-522): δ 10.04 (s, 1H), 8.84 (s, 1H), 8.77-8.75 (d, J=8.4 Hz,1H), 8.46-8.43 (t, J=6.4 Hz, 1H), 8.16 (s, 1H), 7.82 (s, 1H), 7.73-7.66(dd, J=8.4 Hz, 2H), 7.54-7.52 (d, J=8 Hz 1H), 6.99-6.97 (t, J=8.4 Hz,1H), 4.39 (s, 2H), 3.96-3.92 (m, 3H), 3.74-3.73 (d, J=4.8 Hz, 2H),3.65-3.61 (m, 3H), 3.08 (bs, 2H), 3.03-2.98 (m, 2H), 2.34 (s, 6H).

I-820: MS (ES): m/z=532.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6) Isomer-2(I-523): δ 10.05 (s, 1H), 8.84 (s, 1H), 8.74-8.72 (d, J=8.4 Hz, 1H),8.45-8.42 (t, J=6.4 Hz, 1H), 8.16 (s, 1H), 7.82 (s, 1H), 7.73-7.66 (dd,J=8.4 Hz, 2H), 7.54-7.52 (d, J=8 Hz 1H), 6.99-6.97 (t, J=8.4 Hz, 1H),4.39 (s, 2H), 3.96-3.92 (m, 3H), 3.74-3.73 (d, J=4.8 Hz, 2H), 3.65-3.61(m, 3H), 3.08 (bs, 2H), 3.03-2.98 (m, 2H), 2.34 (s, 6H).

Example 30. Method ACp Synthesis of(R)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-45-(3-hydroxytetrahydrofuran-3-yl)pyridin-2-yl)amino)isoindolin-1-one (I-573) and(S)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-45-(3-hydroxytetrahydrofuran-3-yl)pyridin-2-yl)amino)isoindolin-1-one (I-574)

Step-1 Synthesis of tert-butyl 4-chloro-7-((5-(3-hydroxytetrahydrofuran-3-yl)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(30.1)

To a solution of 29.1 (700 mg, 4.1 mmol) in 1-4 dioxane (20 mL) wereadded Intermediate-AA99 (400 mg, 4.1 mmol) and potassium carbonate (1.6g, 12 mmol, 3.0 eq) at RT. After degassing with nitrogen for 20 min,4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (120 mg, 0.41 mmol, 0.1eq) and tris(dibenzylideneacetone)dipalladium(O) (187 mg, 0.41 mmol, 0.1eq) were added. After stirring at 90° C. for 2 h, the reaction was coolto RT; filtered through celite bed and the celite bed washed with ethylacetate (60 mL). The combined organic layers were washed with water (50mL), dried over Na₂SO₄, and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to afford 30.1. (590mg, 53%) as orange solid. MS (ES): m/z 446.3 [M+1]⁺

Step 2, 3 4 and 5 were carried out following representative proceduresdescribed in Example 27 to afford I-573 and I-574.

I-573: (28 mg), MS (ES) m/z 446.8, ¹H NMR (400 MHz, DMSO-d6) δ 10.13 (s,1H), 8.86 (s, 1H), 8.74-8.72 (d, J=8.5 Hz, 1H), 8.51-8.40 (m, 2H),7.89-7.72 (m, 3H), 7.55 (dd, J=10.0, 2.6 Hz, 1H), 7.10-6.93 (m, 2H),5.49 (s, 1H), 4.42 (s, 2H), 4.08-3.96 (m, 2H), 3.85 (d, J=8.8 Hz, 1H),3.77 (d, J=8.9 Hz, 1H), 3.19 (d, J=5.2 Hz, 1H), 2.30 (dt, J=12.7, 9.1Hz, 1H).

I-574: (28 mg), MS (ES) m/z 446.8, 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s,1H), 8.87 (s, 1H), 8.73 (d, J=8.6 Hz, 1H), 8.51-8.38 (m, 2H), 7.89-7.69(m, 3H), 7.55 (dd, J=10.0, 2.6 Hz, 1H), 7.11-6.94 (m, 2H), 5.49 (s, 1H),4.42 (s, 2H), 4.07-3.96 (m, 2H), 3.85 (d, J=8.8 Hz, 1H), 3.77 (d, J=8.8Hz, 1H), 3.19 (d, J=5.2 Hz, 1H), 2.31 (dd, J=12.6, 9.1 Hz, 1H).

Example 31. Method ADp Synthesis of(R)-7-((6-(((2,2-difluoroethyl)amino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-739),(S)-7-((6-(((2,2-difluoroethyl)amino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-740),(R)-7-((6-(((2,2-difluoroethyl)(methyl)amino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-748),(S)-7-((6-(((2,2-difluoroethyl)(methyl)amino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-749)

Step-1 Synthesis of tert-butyl7-((6-(((tert-butoxycarbonyl)(2,2-difluoroethyl)amino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-chloro-1-oxoisoindoline-2-carboxylate(31.1)

To a solution of 3.5 (1.2 g, 3.46 mmol) and Intermediate AA165 (1.2 g,3.46 mmol) in 1,4-dioxane (15 mL) were added Cs₂CO₃ (3.3 g, 10.38 mmol,3.0 eq) and Xantphos (0.4 g, 0.69 mmol, 0.2 eq). After degassing underN2 for 15 min, Pd₂(dba)₃ (0.316 g, 0.34 mmol, 0.1 eq) was added. Afterstirring at 110° C. for 1.5 h, the reaction mixture was cooled to RT,diluted water (30 mL) and extracted with ethyl acetate (30 mL). Theorganic layer was collected, and the aqueous phase was extracted withethyl acetate (2×40 mL). The combined organic extracts were washed withbrine (20 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatography(2-8% methanol gradient in DCM). The residue was then triturated withdiethyl ether and the resulting solid was collected by filtration toafford the title compound 31.1 (1.6 g, 76.48%) as a brown solid. MS(ES): m/z=623.5 [M+2]⁺

Step-2 Synthesis of tert-butyl7-((6-(((tert-butoxycarbonyl)(2,2-difluoroethyl)amino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-1-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate(31.2)

To a solution of 39.1 (0.970 g, 2.57 mmol) in dioxane (20 mL) were addedbis(pinacolato)diboron (1.9 g, 7.71 mmol, 3.0 eq) and potassium acetate(0.755 g, 7.71 mmol, 3.0 eq). After degassing with N2 for 15 min, X-Phospd G2 (0.202 g, 0.25 mmol, 0.1 eq) was added. After stirring at 100° C.for 1 h, the reaction mixture was cooled to RT and diluted ethyl acetate(50 mL) and water (30 mL). The organic layer was collected, and theaqueous phase was extracted with ethyl acetate (2×20 mL). The combinedorganic extracts were washed with brine (10 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure to afford 31.2 (1.2g), which was used in the next step without further purification. MS(ES): m/z 715.36 [M+H]⁺

Step-3 Synthesis of tert-butyl7-((6-(((tert-butoxycarbonyl)(2,2-difluoroethyl)amino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate(31.3)

To a solution of 31.2 (1.2 g, 1.67 mmol) in dioxane (12 mL) and water (2mL) were added Intermediate BB63 (0.87 g, 3.35 mmol, 2.0 eq) andpotassium phosphate tribasic (1.0 g, 5.01 mmol, 3.0 eq). After degassingwith N2 for 15 min, X-Phos Pd G2 (0.125 g, 0.16 mmol, 0.1 eq) was added.After stirring at 110° C. for 2 h, the reaction mixture was cooled to RTand then diluted ethyl acetate (20 mL) and water (20 mL). The organiclayer was collected, and the aqueous phase was extracted with ethylacetate (2×20 mL). The combined organic extracts were washed with brine(20 mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography eluting with3.8% methanol gradient in DCM to afford 31.3 (0.6 g, 49.44%), MS (ES):m/z 723.5[M-41]⁺

Step-4 Synthesis of tert-butyl(S)-7-((6-(((tert-butoxycarbonyl)(2,2-difluoroethyl)amino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate(31.4) and tert-butyl(R)-7-((6-(((tert-butoxycarbonyl)(2,2-difluoroethyl)amino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate(31.5)

31.3 (600 mg) was separated on Waters SFC 200 and UV detector. usingCHIRALPAK IC (250*21.0) mm, 5 micron, at 80.0 mL/min at 100 bar ABPRusing mobile (A) Liquid Carbon dioxide (Liq. CO2) and (B) 0.1% DEA inpropanol:acetonitrile (50:50) to afford compounds 31.4 (200 mg) and 31.5(250 mg). Stereochemistry was arbitrary assigned.

Step-5b Synthesis ofR)-7-((6-(((2,2-difluoroethyl)amino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-739)

To solution of 31.5 (0.250 g, 0.34 mmol,1.0 eq) in DCM (3 mL) was addeddropwise TFA (1.5 mL) at 0° C. After stirring at RT for 30 min, thereaction mixture was neutralized using saturated sodium bicarbonatesolution and extracted with 10% methanol in DCM (3×30 mL). The combineorganic layer was concentrated under reduced pressure and purified bytrituration with n-pentane to afford the title compound I-739 (0.110 g,60.86%) as white solid. MS (ES): m/z 523.20 [M+H]⁺. ¹H NMR (400 MHz,DMSO): δ 10.05 (s, 1H), 8.87 (s, 1H), 8.71-8.69 (d, J=8.8 Hz, 1H),8.44-8.42 (t, J=2.6 Hz, 1H), 7.84 (s, 1H), 7.72-7.70 (d, J=8.8 Hz 1H),7.67-7.65 (d, J=8.4 Hz, 1H), 7.57-7.53 (m, 1H), 7.02-7.01 (d, J=2.8 Hz,1H), 6.94 (s, 1H), 4.40 (s, 2H), 3.99-3.93 (m, 4H), 3.84-3.79 (m, 1H),3.65-3.61 (m, 3H), 3.58-3.54 (m, 1H), 2.99-2.98 (d, J=3.6 Hz, 2H),1.94-1.85 (m, 1H), 1.26 (bs, 1H).

Step-6b Synthesis ofR)-7-((6-(((2,2-difluoroethyl)(methyl)amino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-748)

To a solution I-739 (0.090 g, 0.172 mmol,1.0 eq) in dichloroethane (3mL) at 0° C. were added formaldehyde (0.020 g, 0.688 mmol, 4.0 eq) andacetic acid (0.1 mL). After 20 min, sodium triacetoxyborohydride (0.182g, 0.86 mmol, 5.0 eq) was added portion wise. After stirring at RT for 1h, the reaction mixture was diluted with water (20 mL) and extractedwith ethyl acetate (3×20 mL). The combined organic layer was washed withbrine solution, dried over sodium sulfate, and concentrated underreduced pressure. The residue was purified by reverse phase columnchromatography eluting with 1.8% methanol in DCM to afford the titlecompound I-748 (0.035 g, 37.87%) as White solid. MS (ES): m/z 537.28[M+H]⁺ ¹H NMR (400 MHz, DMSO): δ 10.06 (s, 1H), 8.86 (s, 1H), 8.77-8.75(d, J=8.4 Hz, 1H), 8.46-8.43 (t, J=6.4 Hz, 1H), 7.83 (s, 1H), 7.74-7.71(d, J=8.4 Hz, 1H), 7.69-7.67 (d, J=8.4 Hz, 1H), 7.55-7.52 (d, J=10 Hz,1H), 6.99-6.95 (t, J=7.2 Hz, 2H), 4.39 (s, 2H), 4.01-3.97 (m, 2H),3.83-3.75 (m, 4H), 3.54-3.50 (t, J=7.2 Hz, 3H), 2.87-2.86 (t, J=3.6 Hz,2H), 1.92-1.83 (m, 2H), 1.23 (bs, 2H).

Step-5a Synthesis ofS)-7-((6-(((2,2-difluoroethyl)amino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-740)

To a solution of 31.5 (0.2 g, 0.27 mmol) in DCM (3 mL) at 0° C. wasadded dropwise TFA (1.4 mL). After stirring at RT for 30 min, thereaction mixture was neutralized using saturated sodium bicarbonatesolution and extracted with 10% methanol in DCM (3×20 mL). The combineorganic layer was concentrated under reduced pressure and purified bytrituration with n-pentane to afford the title compound I-740 (0.1 g,69.16%) as white solid. MS (ES): m/z 523.20 [M+H]⁺¹H NMR (400 MHz,DMSO): δ 10.06 (s, 1H), 8.87 (s, 1H), 8.70-8.69 (d, J=8.8 Hz, 1H),8.44-8.42 (t, J=2.6 Hz, 1H), 7.84 (s, 1H), 7.72-7.70 (d, J=8.8 Hz 1H),7.67-7.65 (d, J=8.4 Hz, 1H), 7.57-7.53 (m, 1H), 7.02-7.01 (d, J=2.8 Hz,1H), 6.94 (s, 1H), 4.40 (s, 2H), 3.99-3.93 (m, 4H), 3.84-3.79 (m, 1H),3.65-3.61 (m, 3H), 3.58-3.54 (m, 1H), 2.99-2.98 (d, J=3.6 Hz, 2H),1.94-1.85 (m, 1H), 1.23 (bs, 1H).

Step-6a synthesis ofS)-7-((6-(((2,2-difluoroethyl)(methyl)amino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-749)

To a solution of I-740 (0.080 g, 0.153 mmol,1.0 eq) in dichloroethane (3mL) at 0° C. were added formaldehyde (0.018 g, 0.612 mmol, 4.0 eq) andacetic acid (0.5 mL). After 20 min, sodium triacetoxyborohydride (0.162g, 0.765 mmol, 5.0 eq) was added portion wise. After stirring at RT for1 h, the reaction mixture was diluted with water (20 mL) and extractedwith ethyl acetate (3×20 mL). The combined organic layer was washed withbrine solution, dried over sodium sulfate, and concentrated underreduced pressure. The residue was purified by reverse phase columnchromatography eluting with 2% methanol in DCM to afford the titlecompound I-749 (0.025 g, 30.43%) as white solid. MS (ES): m/z 537.56[M+H]⁺. ¹H NMR (400 MHz, DMSO): δ 10.06 (s, 1H), 8.86 (s, 1H), 8.77-8.75(d, J=8.4 Hz, 1H), 8.46-8.43 (t, J=6.4 Hz, 1H), 7.83 (s, 1H), 7.74-7.71(d, J=8.4 Hz, 1H), 7.69-7.67 (d, J=8.4 Hz, 1H), 7.55-7.52 (d, J=10 Hz,1H), 6.99-6.95 (t, J=7.2 Hz, 2H), 4.39 (s, 2H), 4.01-3.97 (m, 2H),3.83-3.75 (m, 4H), 3.54-3.50 (t, J=7.2 Hz, 3H), 2.87-2.86 (t, J=3.6 Hz,2H), 1.92-1.83 (m, 2H), 1.23 (bs, 2H).

Example 32. Method AEp Synthesis of4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-((R)-24(R)-1-hydroxyethyl)morpholino)pyridin-2-yl)amino)isoindolin-1-one(I-619),4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-((S)-2-((S)-1-hydroxyethyl)morpholino)pyridin-2-yl)amino)isoindolin-1-one(I-620),4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-((R)-24(S)-1-hydroxyethyl)morpholino)pyridin-2-yl)amino)isoindolin-1-one(I-634), and4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-((S)-2-((R)-1-hydroxyethyl)morpholino)pyridin-2-yl)amino)isoindolin-1-one(I-635)

Step-1 Synthesis of tert-butyl4-chloro-7-((5-(2-(1-hydroxyethyl)morpholino)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(32.1) and tert-butyl4-chloro-7-((5-(2-(1-hydroxyethyl)morpholino)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(32.2)

To a solution of 3.5 (2.25 g, 6.4 mmol) and Intermediate AA111 (1.7 mg,7.7 mmol, 1.2 eq) in 1, 4-dioxane (30 mL) was added K₂CO₃ (2.7 g, 19.4mmol, 3 eq). After degassing with N2 for 15 min, Pd₂(dba)₃ (0.594 g,0.64 mmol, 0.05 eq) and Xantphos (0.748 g, 1.2 mmol, 0.2 eq) were added.After stirring at 110° C. for 1.5 h, the reaction mixture was cooled atRT and diluted with water (50 mL) and ethyl acetate (300 mL). Theorganic layer was collected, and the aqueous phase was extract withethyl acetate (30 mL). The combined organic extracts were washed withbrine (20 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatography(1%-2.5% gradient elution MeOH in DCM) to afford diastereomer-1 as 32.1and diastereomer-2 as 32.2.

32.1 was further triturated with diethyl ether to afford 32.1 (2.2 g,45.6%). MS (ES): m/z=489.9 [M+1]+

32.2 was further triturated with diethyl ether to afford 32.2 (1.8 g,66.5%). MS (ES): m/z=489.8 [M+1]+

Step-2 Synthesis of racemic mixture tert-butyl7-((5-(2-(1-hydroxyethyl)morpholino)pyridin-2-yl)amino)-1-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate(32.2)

To a solution of 32.1 (0.97 g, 1.9 mmol) in dioxane (5 mL) were addedbis(pinacolato)diboron (2 g, 7.9 mmol, 4 eq) and potassium acetate(0.586 g, 5.9 mmol, 3.0 eq). After degassing with N2 for 15 min, X-PhosPd G2 (0.072 g, 0.078 mmol, 0.05 eq) was added. After stirring at 110°C. for 2 h, the reaction mixture was cooled at RT and diluted with ethylacetate (20 mL) and water (15 mL). The organic layer was collected, andthe aqueous phase was extracted with ethyl acetate (2×30 mL). Thecombined organic extracts were washed with brine (10 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography (0-1% gradient elution MeOH inDCM) to afford 32.3 (0.900 g), MS (ES): m/z=580.4[M+H]⁺

Step-3 Synthesis of racemic mixture tert-butyl4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-(2-(1-hydroxyethyl)morpholino)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(32.4)

To a solution of 32.3 (0.9 g, 1.5 mmol) in dioxane (8 mL) and water (2mL). were added Intermediate BB63 (0.48 g, 1.8 mmol, 1.2 eq) andpotassium phosphate tribasic (0.98 g, 4.6 mmol, 3.0 eq). After degassingwith N2 for 15 min, X-Phos Pd G2 (0.061 g, 0.07 mmol, 0.05 eq) wasadded. After stirring at 100° C. for 2 h, the reaction mixture wascooled at RT and diluted with ethyl acetate (20 mL) and water (20 mL).The organic layer was collected, and the aqueous phase was extractedwith ethyl acetate (2×30 mL). The combined organic extracts were washedwith brine (20 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with 1.8% methanol gradient in DCM to afford 32.4 (0.420 g,46%), MS (ES): m/z=588.6[M+H]+

Step-4 Synthesis of tert-butyl4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-((R)-24(R)-1-hydroxyethyl)morpholino)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(32.5) and tert-butyl4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-((S)-2-((S)-1-hydroxyethyl)morpholino)pyridin-2-yl)amino)-1-oxoisoindoline-2-carboxylate(32.6)

32.4 (420 mg) was separated on Shimadzu LC-20AP and UV detector usingCHIRALPAK IC (250*21.0) mm column, 5 micron, at 18.0 mL/min using mobilephase (A) 0.1% DEA IN n-Hexane and (B)_(0.1)% DEA inpropanol:acetonitrile (70:30) to afford 32.5 (200 mg) and 32.6 (190 mg).The stereochemistry was arbitrarily assigned.

Step-5a Synthesis of4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-((R)-24(R)-1-hydroxyethyl)morpholino)pyridin-2-yl)amino)isoindolin-1-one(I-619)

To a solution of 32.5 (0.200 g, 0.3 mmol) into DCM (5 mL) at 0° C. wasadded TFA (5 mL). After stirring at RT for 30 min, the reaction mixturewas neutralized using saturated sodium bicarbonate solution andextracted with 10% methanol in DCM (3×20 mL). The combine organic layerwas concentrated under reduced pressure. The residue was purified bycolumn chromatography to afford the title compound I-619 (0.12 g,72%) asan off white solid. MS (ES): m/z 488.5 (M+H). 1H NMR (400 MHz, DMSO-d6)δ 9.89 (s, 1H), 8.80 (s, 1H), 8.58 (d, J=8.5 Hz, 1H), 8.44 (t, J=6.6 Hz,1H), 8.01 (d, J=2.9 Hz, 1H), 7.83 (s, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.50(ddd, J=31.9, 9.5, 2.8 Hz, 2H), 7.04-6.94 (m, 2H), 4.81 (d, J=5.4 Hz,1H), 4.39 (s, 2H), 4.02-3.93 (m, 1H), 3.71-3.51 (m, 2H), 3.42 (dd,J=23.8, 9.3 Hz, 1H), 3.30 (ddd, J=9.9, 7.1, 2.4 Hz, 2H), 2.69 (td,J=11.7, 3.4 Hz, 1H), 2.46 (t, J=10.9 Hz, 1H), 1.19-1.06 (m, 3H).

Step-5b Synthesis of4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-((S)-2-((S)-1-hydroxyethyl)morpholino)pyridin-2-yl)amino)isoindolin-1-one(I-620)

To a solution of 32.6 (0.200 g, 0.3 mmol) in DCM (5 mL) at 0° C. wasadded TFA (5 mL). After stirring at RT for 30 min, the reaction mixturewas neutralized using saturated sodium bicarbonate solution andextracted with 10% methanol in DCM (3×20 mL). The combine organic layerwas concentrated under reduced pressure. The residue was purified bycolumn chromatography to afford the title compound I-620 (0.115 g,72%)as an off white solid. MS (ES): m/z 488.5 (M+H). 1H NMR (400 MHz,DMSO-d6) δ 9.89 (s, 1H), 8.80 (s, 1H), 8.58 (d, J=8.5 Hz, 1H), 8.44 (t,J=6.7 Hz, 1H), 8.04-7.93 (m, 1H), 7.83 (s, 1H), 7.70 (d, J=8.5 Hz, 1H),7.50 (ddd, J=32.0, 9.5, 2.8 Hz, 2H), 7.04-6.94 (m, 2H), 4.81 (d, J=5.3Hz, 1H), 4.39 (s, 1H), 4.01-3.93 (m, 1H), 3.69-3.53 (m, 1H), 3.44 (t,J=13.2 Hz, 1H), 3.35 (s, 3H), 3.30 (ddd, J=9.8, 6.9, 2.3 Hz, 1H), 2.69(td, J=11.7, 3.4 Hz, 1H), 2.46 (t, J=10.9 Hz, 1H), 1.16 (d, J=6.2 Hz,3H).

Synthesis of4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-((R)-2-((S)-1-hydroxyethyl)morpholino)pyridin-2-yl)amino)isoindolin-1-one(I-634) and4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-45-((S)-24(R)-1-hydroxyethyl)morpholino)pyridin-2-yl)amino)isoindolin-1-one(I-635)

I-634 and I-635 were prepared from 32.2 followings step 2, step-3,step-4 and step-5a, step-5b as described above for other diastereomer32.1.

I-634: (106 mg), MS (ES) m/z 489.2, 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s,1H), 8.79 (s, 1H), 8.58-8.56 (d, J=8.6 Hz, 1H), 8.44-8.40 (t, J=6.8 Hz,1H), 8.02-8.01 (d, J=3.0 Hz, 1H), 7.81 (s, 1H), 7.70-7.68 (d, J=8.6 Hz,1H), 7.54-7.48 (ddd, J=24.0, 9.5, 2.8 Hz, 2H), 6.99-6.96 (t, J=8.8 Hz,2H), 4.67-4.65 (d, J=5.1 Hz, 1H), 4.38 (s, 2H), 3.99-3.97 (d, J=10.3 Hz,1H), 3.67-3.62 (m, 2H), 3.50-3.42 (m, 3H), 2.69-2.60 (m, 2H), 1.12-1.10(d, J=6.4 Hz, 3H).

I-635: (117 mg), MS (ES) m/z 489.2, 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s,1H), 8.79 (s, 1H), 8.58-8.56 (d, J=8.6 Hz, 1H), 8.44-8.40 (t, J=6.8 Hz,1H), 8.02-8.01 (d, J=3.0 Hz, 1H), 7.81 (s, 1H), 7.70-7.68 (d, J=8.6 Hz,1H), 7.54-7.48 (ddd, J=24.0, 9.5, 2.8 Hz, 2H), 6.99-6.96 (t, J=8.8 Hz,2H), 4.67-4.65 (d, J=5.1 Hz, 1H), 4.38 (s, 2H), 3.99-3.97 (d, J=10.3 Hz,1H), 3.67-3.62 (m, 2H), 3.50-3.42 (m, 3H), 2.69-2.60 (m, 2H), 1.12-1.10(d, J=6.4 Hz, 3H).

Example 34. Method AHp Synthesis of7-46-((dimethylamino)methyl)-5-(1-methoxycyclopropyl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-823)

Step-1 tert-butyl7-((6-cyano-5-(1-methoxycyclopropyl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate(34.1)

tert-butyl7-((6-cyano-5-(1-methoxycyclopropyl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate34.1 was prepared from tert-butyl7-amino-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate(29.3) and 6-chloro-5-(1-methoxycyclopropyl)picolinonitrile(Intermediate AA203) in a similar fashion to that described in step-1tert-butyl7-((5-(6-(benzyloxy)-1,4-oxazepan-4-yl)-6-((dimethylamino)methyl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate(29.4) (800 mg, 50%). m/z 559.61[M+H]⁺.

Step-2 tert-butyl7-((6-(aminomethyl)-5-(1-methoxycyclopropyl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate(34.2)

To a suspension of Raney nickel (400 mg) in methanol was added 34.1 (800mg, 1.4 mmol, 1 eq). After stirring at 60° C. and at 20 psi for 12 h inautoclave with hydrogen gas, the reaction mixture was filter throughCelite and washed with methanol (200 mL). The filtrate concentratedunder vacuum to afford 34.2 (100 mg, 24.82%). MS (ES): m/z 183.5 [M+1]⁺

Step-3 tert-butyl7-((6-((dimethylamino)methyl)-5-(1-methoxycyclopropyl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate(34.3)

To a solution of Intermediate 34.2 (90 mg, 185.1 mmol) in methanol (1mL) at 0° C. were added paraformaldehyde (450 mg, 2 eq) and acetic acid(cat). After stirring for 30 min. NaCN(BH)₃ (35 mg, 555 mmol, 3 eq) wasadded. After stirring at RT for 4 h, the reaction was washed withaqueous sodium bicarbonate solution (20 mL) and extracted with DCM (2×20mL). The residue was concentrated and purified by silica gelchromatography to afford 34.3. (78 mg, 82%) as orange solid. MS (ES):m/z 587.67 [M+1]⁺

Step-47-46-((dimethylamino)methyl)-5-(1-methoxycyclopropyl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one(I-823)

To a solution of 34.3 (78 mg, 190.08 mmol) in DCM (1 mL) was added TFA(0.3 mL). After stirring at RT for 2 h, the reaction mixture wasevaporated in vacuum and pH adjusted to neutral using NaHCO₃ solution.The aqueous layer extracted by 15% MeOH/DCM. Solvent was evaporatedunder reduced pressure and the residue purified by trituration withdiethyl ether to afford I-823 (27 mg, 41.74%). MS (ES): m/z 487.55.[M+1]⁺. ¹H NMR (400 MHz, DMSO): δ 8.88 (s, 1H), 8.86 (s, 1H), 8.47-8.43(t, J=6 Hz, 1H), 8.19 (s, 1H), 7.84 (s, 1H), 7.75-7.72 (d, J=8.4 Hz,1H), 7.65-7.63 (d, J=8.4 Hz, 1H), 7.53 (bs, 1H), 7.00-6.98 (t, J=5.2 Hz,1H), 6.89 (s, 1H), 4.41 (s, 2H), 3.81 (s, 2H), 3.02 (s, 3H), 1.24 (s,2H), 1.07 (s, 6H), 0.95-0.92 (m, 2H).

Example 35. Method AIp Synthesis of7-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-4-(imidazo[1,2-b]pyridazin-8-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-565)

Step-1 Synthesis of tert-butyl7-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-1-oxo-4-(trimethylstannyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(35.1)

To a solution of 18.1 (0.500 g, 1.08 mmol, 1.0 eq.) in toluene (8 mL)was added hexamethylditin (0.534 g, 1.6 mmol, 1.5 eq.) at RT. Afterdegassing with Argon for 20 min, bis(triphenylphosphine)palladium(II)dichloride (0.076 g, 0.1 mmol, 0.1 eq.) was added. After stirring at110° C. for 8 h, the reaction mixture was poured into water (50 mL) andextracted using ethyl acetate (50 mL×3). The combined organic layer waswashed with brine (50 mL) and concentrated under reduced pressure. Theresidue was purified by column chromatography using basic alumina oxideas a stationary phase eluting with 0.5% methanol in DCM to afford 35.1(450 mg, LCMS: 85%, MS (ES): m/z 588.5 (M+H)+

Step-2 Synthesis of tert-butyl4-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-7-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(35.2)

To a solution of 35.1 (0.450 g, 0.76 mmol) in DMF (8 mL) were addedIntermediate BB82 (0.212 g, 0.91 mmol, 1.2 eq.), tri-o-tolyl phosphine(0.046 g,0.15 mmol, 0.2 eq.) and trimethylamine (0.32 mLg, 2.2 mmol, 3eq) at RT. After degassing with argon for 20 min, Pd₂(dba)₃ (0.070 g,0.076 mmol, 0.1 eq.) was added. After stirring at 110° C. for 3 h, thereaction mixture was poured into water and extracted using ethylacetate. The organic layer was washed with brine (50 mL×3) solution,dried over sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography eluting 2.5% MeOH inDCM to afford 35.2 (0.140 g, 27.81%). MS (ES): m/z 578.6 (M+H)⁺.

Step-3 Synthesis of tert-butyl7-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-4-(imidazo[1,2-b]pyridazin-8-yl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(35.3)

To a solution of 35.2 (0.140 g, 0.243 mmol) in methanol was added 10%Pd/C in autoclave. After heating at 60° C. with 20 psi Hydrogen pressurefor 16 h, the reaction mixture was filter through celite and the celitebed washed with MeOH. The filtrate was concentrated under reducedpressure. The residue was purified by column chromatography eluting with3% methanol in DCM to afford 35.3 (0.070 g). MS (ES): m/z 543.5 (M+H)⁺.

Step-4 Synthesis of7-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-4-(imidazo[1,2-b]pyridazin-8-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-565)

To a solution of 35.3 (0.07 g, 0.129 mmol) in DCM (3 mL) was added 4 MHCl in dioxane (1 mL). After stirring at RT for 2 h, the reactionmixture was neutralized using saturated sodium bicarbonate solutionwhereby a solid precipitated from solution. The solid was collected byfiltration and dried under high vacuum to afford I-565 (0.030 g, 46.08%)as a white solid. MS (ES): m/z 443.18 [M+H]+1H NMR (400 MHz, DMSO-d6) δ9.90 (s, 1H), 9.57 (s, 1H), 9.09 (s, 1H), 8.66-8.65 (d, J=4.8 Hz, 1H),8.43 (s, 1H), 8.07 (d, J=3.1 Hz, 1H), 7.88 (s, 1H), 7.55-7.53 (d, J=4.8Hz, 1H), 7.48-7.47 (dd, J=9.1, 3.0 Hz, 1H), 7.08-7.07 (d, J=8.9 Hz, 1H),4.82 (s, 2H), 4.72-4.71 (d, J=4.2 Hz, 1H), 3.65-3.64 (dq, J=9.1, 4.6 Hz,1H), 3.55-3.47 (m, 3H), 2.88-2.83 (t, J=12.6 Hz, 2H), 1.86 (dd, J=12.8,4.6 Hz, 2H), 1.25 (s, 1H).

Example 36. Method AJp Synthesis of7-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-4-(pyrrolo[1,2-b]pyridazin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-588)

Step-1 Synthesis of tert-butyl7-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-1-oxo-4-(pyrrolo[1,2-b]pyridazin-4-yl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(36.1)

To a stirred solution of 35.1 (0.4 g, 01.38 mmol, 1.0 eq.) andIntermediate BB91 (0.98 g, 1.66 mmol, 1.2 eq.) in t-butanol (5 mL) wasadded cesium fluoride (0.464 g, 3.05 mmol, 2.2 eq.) at RT. Afterdegassing with argon for 20 min, Pd(OAc)₂ (0.062 g,0.27 mmol, 0.2 eq.)and 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphose)(0.284 g, 0.55 mmole, 0.4 eq) was added. After stirring at 110° C. for16 h, the reaction mixture was poured into water (80 mL) and extractedusing ethyl acetate (100 mL×3). The combined organic layer was washedwith brine (50 mL), dried over sodium sulfate, and concentrated underreduced pressure. The residue was purified by combi flash chromatographyeluting 1.5% MeOH in DCM to afford 36.1 (0.220 g, 59.6%). MS (ES): m/z562.7 (M+H)⁺.

Step-27-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-4-(pyrrolo[1,2-b]pyridazin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-588)

I-588 was prepared from 36.1 in a similar fashion to that synthesisdescribed in step-4 of Example 35 (0.025 g, 21%) as a white solid. MS(ES): m/z 442.2 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.56 (s,1H), 9.19 (s, 1H), 8.26-8.25 (d, J=4.7 Hz, 1H), 8.08-8.07 (d, J=3.0 Hz,1H), 7.92 (t, J=2.1 Hz, 1H), 7.49-7.46 (dd, J=9.0, 3.1 Hz, 1H),7.12-7.00 (m, 2H), 7.00-6.93 (m, 2H), 4.78-4.64 (m, 3H), 3.65 (dt,J=8.9, 4.4 Hz, 1H), 3.50 (d, J=11.9 Hz, 2H), 2.92-2.79 (m, 2H), 1.86 (d,J=10.5 Hz, 2H), 1.54 (s, 2H).

Example 37. Method Hc Synthesis of(R)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-226)

Step-1 Synthesis of tert-butyl(R)-4-chloro-7-((5-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)pyridin-2-yl)amino)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(37.1)

A mixture of tert-butyl7-bromo-4-chloro-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(17.2) (430 mg, 1.23 mmol, 1 eq),(R)-2-(1-(6-aminopyridin-3-yl)piperidin-3-yl)propan-2-ol (AC29) (320 mg,1.36 mmol, 1.1 eq), Cs₂CO₃ (805 mg, 12.47 mmol, 2 eq) and4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (71 mg, 0.12mmol, 0.1 eq) was stirred in dry 1,4-dioxane (10 mL) and degassed underN2 stream. After 15 minsTris(dibenzylideneacetone)dipalladium(0)-Pd₂(dba)₃ (113 mg, 0.12 mmol,0.1 eq) was added and the reaction was heated at 110° C. and stirred for1.5 h. The reaction mixture was cooled to RT and then diluted with ethylacetate (50 mL) and water (100 mL). The organic layer was collected andthe aqueous phase was extracted with ethyl acetate (2×50 mL), and thecombined organic extracts were washed with brine (50 mL), then driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Thecrude residue was purified by column chromatography (0-4% gradientelution MeOH in DCM). The residue obtained was then triturated withdiethyl ether and the resulting solid was collected by filtration toafford the title compound 37.1 (150 mg, 26%) as a beige solid. m/z=502.2[M+H]⁺

Step 2: tert-butyl(R)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)pyridin-2-yl)amino)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(37.2)

A mixture of tert-butyl(R)-4-chloro-7-((5-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)pyridin-2-yl)amino)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(37.1) (200 mg, 0.398 mmol),7-fluoro-3-(tributylstannyl)imidazo[1,2-a]pyridine (Intermediate BC9)(254 mg, 0.598 mmol) and Pd(PPh₃)₄ (46 mg, 0.04 mmol) in 1,4-dioxane (4mL) was degassed, purged with nitrogen and heated at 150° C. for 20minutes using microwave irradiation (Biotage Initiator®). The reactionmixture was filtered through Celite concentrated in vacuo and purifiedby silica gel chromatography (gradient: 0-20% methanol in DCM) to affordthe title compound (37.2) (182 mg, 76%) as a pale red solid. This wastaken directly into the next step.

Step 3:(R)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one(I-226)

A solution of tert-butyl(R)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((5-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)pyridin-2-yl)amino)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(37.2) (238 mg, 0.395 mmol) in methanol (6 mL) was treated with ahydrogen chloride solution (4N in 1,4-dioxane, 5.5 mL, 21.82) andstirred at ambient temperature for 1.5 hours. The mixture wasconcentrated in vacuo and dissolved in EtOAc (20 mL). The precipitatethat formed was collected by filtration and purified by preparative HPLCto obtain the title compound (I-226) (18 mg, 9%) as a pale yellow solid.m/z=502 [M+H]⁺, ¹H NMR (400 MHz, DMSO): δ 9.94 (t, J=6.9 Hz, 1H), 9.89(s, 1H), 9.38 (s, 1H), 9.27 (s, 1H), 8.05 (s, 1H), 8.02 (d, J=3.3 Hz,1H), 7.59 (dd, J=2.7, 10.0 Hz, 1H), 7.43 (dd, J=3.2, 9.2 Hz, 1H), 7.14(ddd, J=7.4, 7.4, 2.5 Hz, 1H), 7.01 (d, J=9.2 Hz, 1H), 4.74 (s, 2H),4.29 (s, 1H), 3.76 (d, J=12.0 Hz, 1H), 3.65 (d, J=12.9 Hz, 1H), 2.57(ddd, J=12.6, 12.6, 2.3 Hz, 1H), 2.45 (t, J=11.5 Hz, 1H), 1.86 (d,J=11.4 Hz, 1H), 1.77 (d, J=12.6 Hz, 1H), 1.62-1.54 (m, 2H), 1.21-1.16(m, 1H), 1.14 (s, 3H), 1.12 (s, 3H).

Example 38. Additional Compounds of the Invention

The following compounds were made according to any of the Experimentalmethods A to U as described above in Examples 1-20.

Lengthy table referenced here US20210087189A1-20210325-T00001 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20210087189A1-20210325-T00002 Pleaserefer to the end of the specification for access instructions.

Example 39. Chiral Supercritical Fluid Chromatography (SFC) SeparationProtocol

The diastereomeric/enantiomeric separation of compounds was achieved bySupercritical Fluid Chromatography (SFC) using a Waters Thar Prep100preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV/VISdetector, 2767 liquid handler with Stacked Injection Module).Appropriate columns were selected from LUX Cellulose-4 21.2×250 mm, 5um; YMC Amylose-C 4.6×250 mm, 5 um; YMC Cellulose-C 4.6×250 mm, 5 um; orYMC Cellulose-SC 4.6×250 mm, 5 um. Appropriate isocratic methods wereselected based on methanol, ethanol, or isopropanol solvent systemsunder un-modified or basic conditions. The standard SFC method used wasmodifier, CO2, 100 mL/min, 120 Bar backpressure, 40° C. columntemperature. The modifier used under basic conditions was diethylamine(0.1% V/V). The modifier used under acidic conditions was either formicacid (0.1% V/V) or trifluoroacetic acid (0.1% V/V). The SFC purificationwas controlled by Waters Fractionlynx software through monitoring at210-400 nm and triggered at a threshold collection value, typically 260nm. Collected fractions were analyzed by SFC (Waters/Thar SFC systemswith Waters SQD). The fractions that contained the desired product wereconcentrated by vacuum centrifugation.

Example 40. HPK1 Biochemical Enzyme Assay

HPK1 biochemical enzyme assay: HPK1 enzyme inhibition was measured usinga microfluidic mobility shift assay. Reactions were performed in a384-well plate, containing 1.5 nM HPK1 (Invitrogen), in assay buffer(Carna Biosciences; pH 7.4). Test compounds were titrated in ten pointcurves (top final assay concentration 3 μM), and preincubated withenzyme/substrate mix for 30 min prior to initiation of the reaction byaddition of ATP (1 mM final concentration) and substrate (1 μM finalconcentration; Carna Biosciences) diluted in assay buffer supplementedby MgCl₂ (final assay concentration of 5 mM). Following 60 minincubation at RT, the reaction was terminated by addition of 60 μl/welltermination buffer (Carna Biosciences) and signal determination using aCaliper EZ Reader (Perkin Elmer, UK).

Table 10 shows the activity of selected compounds of this invention inthe HPK1 biochemical enzyme assay. The compound numbers correspond tothe compound numbers in Table 1. Compounds having an activity designatedas “A” provided an IC₅₀≤100 nM; compounds having an activity designatedas “B” provided an IC₅₀>100 nM and ≤1,000 nM; compounds having anactivity designated as “C” provided an IC₅₀>1,000 nM.

TABLE 10 HPK1 Assay results. HPK1 1000UMATP caliper Compound IC50 (nM)I-1 B I-2 B I-3 B I-4 B I-5 B I-6 A I-7 B I-8 B I-9 B I-10 C I-11 B I-12C I-13 B I-14 C I-15 B I-17 C I-18 A I-19 A I-20 A I-21 A I-22 B I-23 BI-24 A I-25 B I-26 B I-27 B I-28 A I-29 A I-30 B I-31 A I-32 A I-33 AI-34 A I-35 B I-36 B I-37 A I-38 A I-39 A I-40 A I-41 A I-42 A I-43 AI-44 B I-45 A I-46 A I-47 A I-48 B I-49 A I-50 B I-51 A I-52 A I-53 BI-55 A I-56 A I-57 A I-58 A I-59 A I-60 A I-61 B I-62 A I-63 A I-64 AI-65 A I-66 B I-67 A I-68 A I-69 A I-70 A I-71 A I-72 A I-73 A I-74 AI-75 A I-76 A I-77 B I-78 B I-79 A I-80 A I-81 A I-82 A I-83 A I-84 AI-85 A I-86 A I-87 A I-88 A I-89 A I-90 A I-91 A I-92 A I-93 A I-94 AI-95 A I-96 A I-97 A I-98 A I-99 B I-100 A I-101 A I-102 A I-103 B I-104A I-105 A I-106 A I-107 A I-108 A I-109 A I-110 A I-111 A I-112 A I-113A I-114 C I-115 A I-116 A I-117 A I-118 B I-119 A I-120 A I-121 A I-122A I-123 A I-124 A I-125 A I-126 A I-127 C I-128 A I-129 A I-130 A I-131A I-132 C I-133 A I-134 A I-135 A I-136 A I-137 A I-138 A I-139 A I-140A I-141 A I-142 A I-143 A I-144 A I-145 A I-146 A I-147 B I-148 A I-149A I-150 B I-151 A I-152 A I-153 A I-154 A I-155 A I-156 A I-157 A I-158A I-159 A I-160 A I-161 A I-162 A I-163 B I-164 A I-165 C I-166 A I-167A I-168 A I-169 A I-170 A I-171 A I-172 A I-173 A I-174 A I-175 A I-176A I-177 A I-178 A I-179 A I-180 B I-181 A I-182 A I-183 A I-184 A I-185B I-186 A I-187 A I-188 A I-189 B I-190 A I-191 A I-192 A I-193 A I-194A I-195 B I-196 A I-197 A I-198 B I-199 B I-200 A I-201 A I-202 A I-203A I-204 A I-205 B I-206 B I-207 B I-208 B I-209 A I-210 A I-211 A I-212A I-213 A I-214 A I-215 B I-216 A I-217 A I-218 A I-219 A I-220 A I-221A I-222 A I-223 A I-224 A I-225 A I-226 B I-227 A I-228 B I-229 A I-230A I-231 A I-232 A I-233 A I-234 B I-235 A I-236 A I-237 B I-238 A I-239B I-240 B I-241 A I-242 A I-243 A I-244 A I-245 A I-246 A I-247 A I-248C I-249 B I-250 B I-251 A I-252 B I-253 C I-254 B I-255 A I-256 A I-257B I-258 A I-259 B I-260 C I-261 A I-262 A I-263 A I-264 A I-265 A I-266A I-267 C I-268 B I-269 A I-270 B I-271 A I-272 A I-273 C I-274 A I-275A I-276 A I-278 A I-279 A I-280 A I-281 A I-282 C I-283 B I-284 A I-285A I-286 C I-287 A I-288 B I-289 A I-290 C I-291 A I-292 A I-293 A I-294A I-295 A I-296 B I-297 A I-298 A I-299 A I-300 A I-301 A I-302 B I-303A I-304 A I-305 C I-306 C I-307 B I-308 C I-309 A I-310 A I-311 A I-312A I-313 A I-314 A I-315 A I-316 C I-317 A I-318 A I-319 A I-320 A I-321A I-322 A I-323 C I-324 C I-325 A I-326 A I-327 A I-328 A I-329 A I-330B I-331 A I-332 A I-333 A I-334 A I-335 A I-336 A I-338 A I-339 A I-340C I-341 A I-343 A I-344 A I-345 A I-346 A I-347 A I-348 A I-349 A I-350A I-351 A I-352 A I-353 B I-354 C I-355 A I-356 A I-357 A I-358 A I-359A I-360 A I-361 A I-362 A I-363 A I-364 A I-365 A I-366 A I-367 A I-368C I-369 A I-370 B I-371 A I-372 A I-373 A I-374 A I-375 C I-376 B I-377B I-378 B I-379 B I-380 B I-381 A I-382 C I-383 A I-384 C I-385 A I-386A I-387 A I-388 A I-389 A I-390 B I-391 A I-392 A I-393 A I-394 A I-395A I-396 C I-397 A I-398 B I-399 A I-400 A I-401 A I-402 A I-403 A I-404A I-405 A I-406 A I-407 A I-408 A I-411 A I-412 A I-413 C I-414 A I-415A I-416 A I-417 A I-418 C I-419 C I-420 A I-421 A I-422 B I-423 A I-424A I-425 A I-426 A I-427 A I-428 A I-429 A I-430 C I-431 A I-432 C I-433A I-434 A I-435 A I-436 A I-437 A I-438 A I-439 A I-440 A I-441 B I-442A I-443 A I-444 A I-445 B I-446 A I-447 A I-448 B I-449 A I-450 A I-451A I-452 A I-453 A I-454 A I-455 B I-456 A I-457 A I-458 A I-459 A I-460A I-461 A I-462 A I-463 A I-464 A I-465 A I-467 A I-468 A I-469 A I-470C I-471 A I-472 A I-473 A I-474 A I-475 A I-476 A I-477 A I-478 A I-479A I-480 B I-481 A I-482 A I-483 A I-484 A I-485 A I-486 A I-487 A I-488A I-489 A I-490 A I-491 A I-492 A I-493 A I-494 A I-495 A I-496 A I-497A I-498 A I-499 A I-500 A I-501 A I-502 A I-503 A I-504 A I-505 A I-506aA I-506 A I-507 A I-508 A I-509 A I-510 A I-511 A I-512 A I-513 A I-514A I-515 A I-516 A I-517 A I-518 A I-519 A I-520 A I-521 A I-522 A I-523A I-524 A I-525 A I-526 A I-527 A I-528 A I-529 A I-530 A I-531 A I-532A I-533 A I-534 A I-535 A I-536 A I-537 A I-538 A I-539 A I-540 A I-541A I-542 A I-543 A I-544 A I-545 A I-546 A I-547 A I-548 A I-549 A I-550A I-551 A I-552 A I-553 A I-554 A I-555 A I-556 A I-557 A I-558 A I-559A I-560 A I-561 A I-562 A I-563 A I-564 A I-565 C I-566 A I-567 A I-568A I-569 A I-570 A I-571 A I-572 A I-573 A I-574 A I-575 B I-576 A I-577A I-578 A I-579 A I-580 A I-581 A I-582 A I-583 A I-584 A I-585 A I-586A I-587 A I-588 C I-589 A I-590 A I-591 A I-592 C I-593 A I-594 A I-595A I-596 A I-597 A I-598 A I-599 A I-600 A I-601 A I-602 A I-603 A I-604A I-605 A I-606 A I-607 A I-608 A I-609 A I-610 A I-611 A I-612 A I-613A I-614 A I-615 B I-616 A I-617 A I-618 A I-619 A I-620 A I-621 A I-622A I-623 A I-624 A I-626 A I-627 A I-628 A I-629 A I-630 A I-631 C I-632C I-633 A I-634 A I-635 A I-639 A I-640 A I-641 A I-642 B I-643 A I-644B I-645 A I-646 A I-648 A I-649 A I-650 A I-651 B I-652 A I-653 A I-654A I-655 A I-656 A I-657 A I-658 A I-659 A I-660 A I-661 B I-662 A I-663A I-667 C I-668 A I-669 A I-670 A I-671 A I-672 A I-673 A I-674 A I-675A I-676 A I-677 A I-678 A I-679 A I-680 B I-681 A I-682 B I-683 A I-684A I-685 B I-686 A I-687 A I-688 C I-689 B I-690 A I-691 A I-692 A I-693A I-694 A I-695 A I-696 A I-697 A I-698 A I-699 A I-700 A I-701 A I-702A I-703 A I-704 A I-705 A I-706 A I-707 A I-708 A I-709 A I-710 A I-711A I-712 A I-713 A I-714 A I-715 A I-716 A I-717 A I-718 A I-719 A I-720A I-721 A I-722 A I-723 A I-724 B I-725 A I-726 A I-727 A I-728 A I-729A I-730 A I-731 A I-732 A I-733 A I-734 A I-735 A I-736 A I-737 A I-738A I-739 A I-740 A I-741 A I-742 A I-743 A I-744 A I-745 A I-746 A I-747A I-748 A I-749 A I-750 A I-751 A I-752 A I-753 A I-754 A I-755 A I-756A I-757 A I-758 A I-759 A I-760 A I-761 A I-762 A I-763 A I-764 A I-765A I-766 A I-767 A I-768 A I-769 A I-770 A I-771 A I-772 A I-773 B I-774A I-775 A I-776 A I-777 A I-778 A I-779 A I-780 A I-781 A I-782 A I-783A I-784 A I-785 A I-786 A I-787 A I-788 A I-789 A I-790 A I-791 A I-792A I-793 A I-794 A I-795 A I-796 A I-797 A I-798 A I-799 A I-800 A I-801A I-802 A I-803 A I-804 A I-805 A I-806 A I-807 A I-808 A I-809 A I-810A I-811 A I-812 A I-813 A I-814 A I-815 A I-816 A I-817 A I-818 B I-819A I-820 A I-821 A I-822 A I-823 A I-824 A I-825 A I-826 A I-827 A I-828A I-829 A I-830 A I-831 A I-832 B I-833 B I-834 A I-835 A I-836 A I-837A I-838 A I-839 A I-840 A I-841 B I-842 A I-843 A I-844 A I-845 A I-846A I-847 A I-848 A I-849 A I-850 A I-851 A I-852 A

While we have described a number of embodiments of this invention, it isapparent that our examples may be altered to provide other embodimentsthat utilize the compounds and methods of this invention. Therefore, itwill be appreciated that the scope of this invention is to be defined bythe appended claims rather than by the specific embodiments that havebeen represented by way of example.

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(https://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20210087189A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

We claim: 1-34. (canceled)
 35. A compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.
 36. The compound of claim35, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 37. The compound of claim35, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 38. The compound of claim35, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 39. The compound of claim35, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 40. The compound of claim35, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 41. The compound of claim35, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 42. The compound of claim35, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 43. The compound of claim35, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 44. The compound of claim35, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 45. The compound of claim35, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 46. A pharmaceuticalcomposition comprising a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.
 47. The pharmaceuticalcomposition of claim 46, wherein said compound is

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.
 48. The pharmaceuticalcomposition of claim 46, wherein said compound is

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.
 49. The pharmaceuticalcomposition of claim 46, wherein said compound is

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.
 50. The pharmaceuticalcomposition of claim 46, wherein said compound is

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.
 51. The pharmaceuticalcomposition of claim 46, wherein said compound is

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.
 52. The pharmaceuticalcomposition of claim 46, wherein said compound is

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.
 53. The pharmaceuticalcomposition of claim 46, wherein said compound is

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.
 54. The pharmaceuticalcomposition of claim 46, wherein said compound is

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.
 55. The pharmaceuticalcomposition of claim 46, wherein said compound is

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.
 56. The pharmaceuticalcomposition of claim 46, wherein said compound is

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.